2-substituted thiazolidinones as β-3 adrenergic receptor agonists

ABSTRACT

This invention provides compounds of Formula I having the structure                    
     wherein: 
     A, X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are as defined hereinbefore or a pharmaceutically acceptable salt thereof, which are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.

This application is a divisional of U.S. application Ser. No.10/132,483, filed Apr. 25, 2002 now U.S. Pat. No. 6,583,140, which is adivisional of U.S. application Ser. No. 09/904,157, filed Jul. 12, 2001,now U.S. Pat. No. 6,410,734. The '157 application claims the benefit ofU.S. Provisional Application No. 60/218,724, filed Jul. 17, 2000.

BACKGROUND OF THE INVENTION

This invention relates to 2-substituted thiazolidinone derivatives whichare β₃ adrenergic receptor agonists useful for the treatment ofmetabolic disorders related to insulin resistance or hyperglycemia(typically associated with obesity or glucose intolerance),atherosclerosis, gastrointestinal disorders, neurogenetic inflammation,and frequent urination, and are particularly useful in the treatment orinhibition of type II diabetes.

The subdivision of β adrenergic receptors (β-AR) into β₁- and β₂-AR hasled to the development of β₁- and β₂-antagonists and/or agonists whichhave been useful for the treatment of cardiovascular disease and asthma.The recent discovery of “atypical” receptors, later called β₃-AR, hasled to the development of β₃-AR agnoists which may be potentially usefulas antiobesity and antidiabetic agents. For recent reviews on β₃-ARagnoists , see: 1. A. D. Strosberg, Annu. Rev. Pharmacol. Toxicol. 1997,37,421; 2. A. E. Weber, Ann. Rep. Med. Chem. 1998, 33, 193; 3. C. P.Kordik and A. B. Reitz, J. Med. Chem. 1999, 42, 181; 4. C. Weyer, J. F.Gautier and E. Danforth, Diabetes and Metabolism, 1999, 25, 11.

Compounds that are potent and selective β₃ agonists, may be potentiallyuseful antiobesity agents. Low levels or lack of β₁ and β₂-agonisticproperties will minimize or eliminate the adverse side effects that areassociated with β₁ and β₂ agonistic activities, i.e. increased heartrate, and muscle tremor, respectively. Early developments in theβ₃-agonist field are described in European patent 427480, U.S. Pat. Nos.4,396,627, 4,478,849, 4,999,377, 5,153,210. Although the earlydevelopments purport to claim compounds with greater β₃-AR selectivityover the β₁- and β₂-AR. However, clinical trials in humans with thoseearly developed β₃-agonists have, so far, not been successful.

More recently, potent and selective human β₃ agonists have beendescribed in several patents and published applications: WO 98/32753, WO97/46556, WO 97/37646, WO 97/15549, WO 97/25311, WO 96/16938, WO95/29159, European Patents 659737, 801060, 714883, 764640, 827746, andU.S. Pat. Nos. 5,561,142, 5,705,515, 5,436,257, and 5,578,620. Thesecompounds were evaluated in Chinese hamster ovary (CHO) cells testprocedures, expressing cloned human β₃ receptors, which predict theeffects that can be expected in humans (Granneman et al., MolPharmacol., 1992, 42, 964; Emorine et al., Science, 1989, 245, 1118;Liggett Mol. Pharmacol., 1992, 42, 634).

β₃-Adrenergic agonists also are useful in controlling the frequent urgeof urination. It has been known that relaxation of the bladder detrusoris under beta adrenergic control (Li J H, Yasay G D and Kau S TPharmacology 1992; 44: 13-18). Beta-adrenoceptor subtypes are in thedetrusor of guinea-pig urinary bladder. Recently, a number oflaboratories have provided experimental evidence of β₃ adrenergicreceptors in a number of animal species including human (Yamazaki Y,Takeda H, Akahane M, Igawa Y, et al. Br. J. Pharmacol. 1998; 124:593-599), and that activation of the β₃ receptor subtype bynorepinephrine is responsible for relaxation of the urinary bladder.

Urge urinary incontinence is characterized by abnormal spontaneousbladder contractions that can be unrelated to bladder urine volume. Urgeurinary incontinence is often referred to hyperactive or unstablebladder. Several etiologies exist and fall into two major categories,myogenic and neurogenic. The myogenic bladder is usually associated withdetrusor hypertrophy secondary to bladder outlet obstruction, or withchronic urinary tract infection. Neurogenic bladders are associatedwith, an uninhibited micturition reflex. An upper motor neuron diseaseis usually the underlying cause. In either case, the disease ischaracterized my abnormal spontaneous contractions that result in anabnormal sense of urinary urgency and involuntary urine loss. Atpresent, the most common therapy for hyperactive bladder includes theuse of antimuscarinic agents to block the action of the excitatoryneurotransmitter acetylcholine. While effective in neurogenic bladders,their utility in myogenic bladders is questionable. In addition, due tosevere dry mouth side-effects associated with antimuscarinic therapy,the patient compliance with these agents is only approximately 30%.

In the bladder, β₃ adrenergic receptor agonists activate adenylylcyclase and generate cAMP through the G-protein coupled β₃ receptor. Theresulting phosphorylation of phospholamban/calcium ATPase enhancesuptake of calcium into the sarcoplasmic reticulum. The decrease inintracellular calcium inhibits bladder smooth muscle contractility.

It is suggested therefore, that activation of the β₃ adrenergic receptorin the urinary bladder will inhibit abnormal spontaneous bladdercontractions and be useful for the treatment of bladder hyperactivity.Note, that unlike the antimuscarinics, β₃ adrenergic receptor agonistswould be expected to be active against both neurogenic and myogenicetiologies.

Despite all these recent developments there is still no single therapyavailable for the treatment of type II diabetes (NIDDM), obesity,atherosclerosis, gastrointestinal disorders, neurogenetic inflammation,frequent urination and related diseases. A potent and selective β₃adrenergic receptor agonist is therefore highly desirable for thepotential treatment of such disease states.

DESCRIPTION OF THE INVENTION

This invention provides compounds of Formula I having the structure

wherein:

A is aryl or Het;

X is —OCH₂—, —SCH₂—, or a bond;

Y is alkyl of 1-6 carbon atoms, alkyloxy of 1-6 carbon atoms, azetidine,pyrrolidine or piperidine; wherein the nitrogen of the azetidine,pyrrolidine or piperidine attached to the adjacent phenyl ring;

Z is S, O, NH or N-alkyl of 1-6 carbon atoms;

R₁, R₂, and R₃ are each, independently, hydrogen, alkyl of 1-6 carbonatoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen,trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy,propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino,aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbonatoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino,dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, ordihydroxyphosphorylamino, or two of the three substituents (R₁, R₂ andR₃) combine with the carbon to which each is attached to form a arylfused cycloalkyl of 3-8 carbon atoms optionally substituted withacylamino or hydroxy;

R₄ is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms,hydroxy, carboxy, or halogen;

R₅ is hydrogen or alkyl of 1-6 carbon atoms;

R₆ is (i) SCH₃ or NR₇R₈; (ii) an amino acid, wherein the nitrogen ofamino acid is attached to the adjacent thiazolidinone, oxazolidinone, orimidazolidinone ring; (iii) an alkyl ester of an amino acid, wherein thenitrogen of amino acid is attached to the adjacent thiazolidinone,oxazolidinone, or imidazolidinone ring, and the alkyl moiety of thealkyl ester contains 1-6 carbon atoms; or (iv) NH(C═Q)NR₇R₈ orNHNH(C═Q)NR₇R₈;

R₇ and R₈ are each, independently, hydrogen, aryl, Het, alkyl of 1-6carbon atoms, arylalkyl in which the alkyl moiety has 1-6 carbon atoms,Hetalkyl in which the alkyl moiety has 1-6 carbon atoms, haloalkyl of1-6 carbon atoms, dialkylaminoalkyl of 1-6 carbon atoms per alkyl group,hydroxy, alkoxy of 1-6 carbon atoms, benzyloxy, cyano, alkylamino of 1-6carbon atoms, dialkylamino having 1-6 carbon atoms per alkyl group,acylamino of 2-7 carbon atoms, alkylsulfonylamino of 1-6 carbon atoms;or R₇ and R₈ are taken together with the nitrogen to which each isattached to form a saturated, unsaturated, or partially unsaturated 3-8membered heterocyclic ring optionally containing 1 to 3 additionalheteroatoms selected from S, O, and N, and optionally substituted withR₉;

Q is O, S, NH, NCN; or Q and one of R₇ and R₈ are taken together to forma partially unsaturated or unsaturated 3-8 membered heterocyclic ringoptionally containing 1-2 additional heteroatoms selected from S, O, andN, and optionally substituted with R₉;

Het is a monocyclic or bicyclic heterocycle of 5-10 ring atoms, having1-4 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein theheterocycle may be saturated, unsaturated, or partially unsaturated; maybe optionally fused to a phenyl ring, and may be optionally substitutedwith R₉;

R₉ is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms,arylalkyl having 1-6 carbon atoms in the alkyl group, hydroxy, halogen,trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy,propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino,aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbonatoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino,dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, ordihydroxyphosphorylamino;

or a pharmaceutically acceptable salt thereof, which are selectiveagonists at human β₃ adrenergic receptors and are useful in treating orinhibiting metabolic disorders related to insulin resistance orhyperglycemia (typically associated with obesity or glucoseintolerance), atherosclerosis, gastrointestinal disorders, neurogeneticinflammation, and frequent urination; and are particularly useful in thetreatment or inhibition of type II diabetes.

Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids when a compound ofthis invention contains a basic moiety. Salts may also be formed fromorganic and inorganic bases, such as alkali metal salts (for example,sodium, lithium, or potassium), alkaline earth metal salts, ammoniumsalts, alkylammonium salts containing 1-6 carbon atoms ordialkylammonium salts containing 1-6 carbon atoms in each alkyl group,and trialkylammonium salts containing 1-6 carbon atoms in each alkylgroup, when a compound of this invention contains an acidic moiety.

Alkyl includes both straight chain as well as branched moieties. Bydefinition alkyl also includes alkyl moieties which are optionally mono-or poly substituted with groups such as halogen, hydroxy, cyano, alkoxy,aryloxy, arylalkyl, alkylthio, arylthio, amino, alkylamino, anddialkylamino. Halogen means bromine, chlorine, fluorine, and iodine.Where a substituent contains one or more moieties which have the samedesignation, each of the moieties can be the same or different.

Preferred aryl moieties include phenyl or naphthyl. Preferred Hetmoieties include: (a) 6-membered saturated, partially unsaturated, orunsaturated heterocycles containing 1-2 nitrogens, optionally fused to aphenyl ring; (b) 5-membered saturated, partially saturated, orunsaturated heterocycles containing 1-3 nitrogen, oxygen, or sulfuratoms, optionally fused to a phenyl ring; (c) saturated, partiallyunsaturated, or unsaturated bicyclic heterocycles containing 1-4nitrogen, oxygen, or sulfur atoms; (d) carbazole, dibenzofuran, anddibenzothiophene. In the Het of categories (a), (b), and (c), ringcarbon atoms may be carbonyl moieties, where the ring does not contain adouble bond in that position (for example, thiazolidine-2,4-dione).

More preferred Het rings include pyrrole, furan, thiophene, imidazole,pyrazole, furazan, triazole, tetrazole, oxazoel, oxadiazole, isoxazole,thiazole, isothiazole, thiadiazole, pyridine, pyrimidine, pyridazine,pyrazine, 1,3,5-triazine, 1,2,4,5-tetrazine, benzofuran, isobenzofuran,indole, isoindole, benzothiophene, benzimidazol, 3H-benzoxazol-2-one,benzotriazole, quinoline, isoquinoline, quinazoline, indazole,1H-quinolin-2-one, 3,4-dihydro-1H-quinolin-2-one, 2,3-dihydro-1H-indole,1,3-dihydro-benzoimidazol-2-one, 1,3-dihydro-benzoimidazol-2-thione, andcarbazole. It is understood that Het do not contain heteroatoms inarrangements which would make them inherently unstable. For example, theterm Het does not include ring systems containing O—O bonds in the ringbackbone.

Preferred amino acids include alanine, valine, leucine, isoleucine,proline, phenylalanine, tryptophan, methionine, glycine, serine,threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid,glutamic acid, lysine, arginine, histidine, β-alanine, cyclopropaneamino acids (such as 1-aminocyclopropane-1-carboxylic acid,allo-coronamic acid and 2,3-methanohomoserine),1-aminocyclohexane-1-carboxylic acid, isonipecotic acid,2-azetidinecarboxylic acid.

The compounds of the present invention contain at least one asymmetriccenter. Additional asymmetric centers may exist on the moleculedepending upon the structure of the substituents on the molecule. Thecompounds may be prepared as a racemic mixture and can be used as such,or may be resolved into all individual steroisomers. In addition tocovering the racemic compounds, this invention also covers allindividual isomers, enantiomers, diasteromers or mixtures thereof,regardless of whether the structural representations of the compoundsindicate such stereochemistry.

The compounds of the present invention may also contain geometricisomers. Thus, the present invention includes all individual isomers andmixtures thereof.

Preferred compounds of Formula I are those in which

A is phenyl or Het;

X is —OCH₂—, or a bond;

Y is alkyl of 1-6 carbon atoms, alkyloxy of 1-6 carbon atoms, orpiperidine;

Z is S, O, NH or N-alkyl of 1-6 carbon atoms;

R₁, R₂, and R₃ are each, independently, hydrogen, alkyl of 1-6 carbonatoms, hydroxy, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms,acyloxy of 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl,alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms peralkyl group, formamido, ureido, acylamino of 2-7 carbon atoms, oralkylsulfonylamino of 1-6 carbon atoms;

R₄ is hydrogen;

R₅ is hydrogen;

R₆ is (i) NR₇R₈; (ii) an amino acid, wherein the nitrogen of amino acidattached to the adjacent thiazolidinone, oxazolidinone, orimidazolidinone ring; (iii) an alkyl ester of an amino acid, wherein thenitrogen of amino acid attached to the adjacent thiazolidinone,oxazolidinone, or imidazolidinone ring, and the alkyl moiety of thealkyl ester contains 1-6 carbon atoms; or (iv) NH(C═Q)NR₇R₈;

R₇ and R₈ are each, independently, hydrogen, Het, alkyl of 1-6 carbonatoms, Hetalkyl in which the alkyl moiety has 1-6 carbon atoms,dialkylaminoalkyl of 1-6 carbon atoms per alkyl group, cyano, hydroxy,or alkylamino of 1-6 carbon atoms; or R₇ and R₈ are taken together withthe nitrogen to which each is attached to form a saturated, unsaturated,or partially unsaturated 3-8 membered heterocyclic ring optionallycontaining 1 to 3 additional heteroatoms selected from S, O and N, andoptionally substituted with R₉;

Q is O, S, NH, NCN;

Het is (a) a 6-membered saturated, partially unsaturated, or unsaturatedheterocycle containing 1-2 nitrogens, optionally fused to a phenyl ring;(b) a 5-membered saturated, partially saturated, or unsaturatedheterocycle containing 1-3 nitrogen, oxygen, or sulfur atoms, optionallyfused to a phenyl ring; (c) a saturated, partially unsaturated, orunsaturated bicyclic heterocycle containing 1-4 nitrogen, oxygen, orsulfur atoms; (d) carbazole, dibenzofuran, and dibenzothiophene; whereinone or more of the ring carbon atoms of Het as described in (a), (b), or(c) may be a carbonyl moiety, where the ring does not contain a doublebond in the position corresponding to that carbon atom; wherein Het maybe optionally substituted by R₉;

R₉ is alkyl of 1-6 carbon atoms, or arylalkyl having 1-6 carbon atoms inthe alkyl group;

or a pharmaceutically acceptable salt thereof.

Specifically preferred compounds of this invention are:

a)4-((2S)-2-hydroxy-3-{1-[4-(2-methylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one;

b)4-[(2S)-2-hydroxy-3-(1-{4-[2-(2-morpholin-4-yl-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-propoxy]-1,3-dihydro-benzoimidazol-2-one;

c)4-[(2S)-3-(1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-2-hydroxy-propoxy]-1,3-dihydro-benzoimidazol-2-one;

d)2-(1-benzyl-piperidin-4-ylamino)-5-(4-{(2S)-4-[2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazol-4-one;

e)N-{5-[2-(1-{4-[2-(1-benzyl-piperidin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}-methanesulfonamide;

f)N′-[5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-yl]-N,N-dimethyl-guanidine;

g)N-{5-[2-(1-{4-[2-(N′,N′-dimethyl-guanidino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}methanesulfonamide;

h)3-[5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-propionicacid ethyl ester;

i)3-[5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-propionicacid;

j)4-((2S)-2-hydroxy-3-{1-[4-(2-hydroxyamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one;

k)N-[2-hydroxy-5-(1-hydroxy-2-{1-[4-(2-hydroxyamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;

l)4-((2S)-2-hydroxy-3-{1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one;

m)N-[2-hydroxy-5-((1R)-1-hydroxy-2-{1-[4-(4-oxo-2-piperidin-1yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;

n)N-[2-hydroxy-5-((2S)-2-hydroxy-3-{1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-phenyl]-methanesulfonamide;

o)8-hydroxy-5-((2S)-2-hydroxy-3-{1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-3,4-dihydro-1H-quinolin-2-one;

p)5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-piperidin-1-yl-thiazol-4-one;

q)N′-[5-(4-{4-[(2S)-2-hydroxy-3-(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-5-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-yl]-N,N-dimethyl-guanidine;

r)4-((2S)-2-hydroxy-3-{1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one;

s)4-[(2S)-2-hydroxy-3-(1-{4-[2-(4-methyl-piperidin-1-yl)-4-oxo-4H-thiazol-5ylidenemethyl]-phenyl}-piperidin-4-ylamino)-propoxy]-1,3-dihydro-benzoimidazol-2-one;

t)N′-(5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2-yl)-N,N-dimethyl-guanidine;

u)N′-[5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-yl]-N,N-dimethyl-guanidine;

v)5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-2-morpholin-4-yl-thiazol-4-one;

w)5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-morpholin-4-yl-thiazol-4-one;

x)5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-(4-methyl-piperazin-1-yl)-thiazol-4-one;

y)5-(4-{4-[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-benzylidene)-2-morpholin-4-yl-thiazol-4-one;

z) 2-(3-dimethylamino-propylamino)-5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-thiazol-4-one;

aa)2-hexylamino-5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-thiazol-4-one;

bb)N-[5-((2R)-2-{1-[4-(2-cyanoamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide;

cc)(2S)-2-[5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-pentanedioicacid;

dd)(2S)-2-[5-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-pentanedioicacid diethyl ester;

ee)5-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethoxy}-benzylidene)-2-piperidin-1-yl-thiazol-4-one;

ff)5-{4-[2-((2S)-2-hydroxy-3-phenoxy-propylamino)-ethoxy]-benzylidene}-2-piperidin-1-yl-thiazol-4-one;

gg)N-[2-hydroxy-5-(1-hydroxy-2-{2-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;and

hh)8-hydroxy-5-((2S)-2-hydroxy-3-{2-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenoxy]-ethylamino}-propoxy)-3,4-dihydro-1H-quinolin-2-one

or a pharmaceutically acceptable salt thereof.

The compounds of this invention were prepared according to the followingschemes from commercially available starting materials or startingmaterials which can be prepared using literature procedures. Theseschemes show the preparation of representative compounds of thisinvention.

According to one route (Scheme 1), 1,4-dioxa-8-azaspiro[4,5]decane isreacted with 4-fluorobenze 1 in the presence of base such as pyridine orpotassium carbonate to afford piperidine derivative 2 (Taylor, E. C.,Skotnicki, J. S. Synthesis 1981, 606). This reaction can be carried outin a polar solvent such as anhydrous acetonitrile, acetone,dimethylformamide, or pyridine. Compound 4 is obtained via a Knoevenagelcondensation between an appropriate cyclic lactam 3 and the piperidinederivative 2. In this reaction sodium acetate, β-alanine, glycine,pyridine, piperidine, pyrrolidine, sodium methoxide, potassium acetate,sodium carbonate and the like can be used as a base, and an alcohol suchas methanol, ethanol, isopropanol, methoxyethanol and the like,dimethylformamide, water, acetic acid and the like can be used as asolvent.

Arylidene compound 6 can be prepared by one of the following syntheticmethods (Unangst, P. C., Connor, D. T., Cetenko, W. A., Sorenson, R. J.,Kostlan, C. R., Sircar, J. C., Wright, C. D., Schrier, D. J., Dyer, R.D. J. Med. Chem. 1994, 37, 322). One method is a condensation of lactam4 with amines such as hydroxylamine, N-alkylhydroxyamine,O-alkylhydroxyamine and the like in an alcoholic solvent such asmethanol, ethanol, isopropanol and the like at a temperature of 20-100°C. The reaction is conveniently conducted in refluxing methanol orethanol. Alternatively, alkylation of lactam 4 with iodomethane providesmethylmercapto compound 5. Reaction of compound 5 with various aminessuch as methylamine, 4-(2-aminoethyl)morpholine, piperidine and the likein an alcoholic solvent at a temperature of 20-100° C. gives the desiredintermediate 6. The reaction is also conveniently conducted in refluxingmethanol or ethanol.

Many amines are commercially available in the hydrochloride salt orsulfate form. Free amines can be easily obtained by methods well knownin the art. For example, treatment of N,N-dimethylguanidine sulfate witha stoichiometric equivalent of potassium t-butoxide in ethanol followedby a quick filtration would produce an alcoholic amine solution.Refluxing of methylmercapto compound 5 with the alcoholic amine solutiongives the desired intermediate 6.

Ketal hydrolysis is accomplished in the presence of strong acid such asconcentrated hydrochloric acid or 10-30% sulfuric acid. The desiredfinal product 9, wherein A, R₁, R₂, R₃, R₄, R₅, R₆, X and Z are asdefined above, is prepared by utilizing reductive amination ofpiperidiones 7 with appropriate arylethanolamines oraryloxypropanolamines 8. The reductive amination can be carried out, forexample, with hydrogen and catalytic palladium, or with sodiumborohydride, sodium triacetoxyborohydride and the like in a polarsolvent such as methanol, dimethylformamide and the like. The finalproducts can be purified by recrystallization, trituration, preparativethin layer chromatography, flash column chromatography on silica gel, orhigh pressure liquid chromatography. Purification of intermediates canbe achieved in the same manner. A salt is optionally produced by theaddition of an acid or base, such as hydrogen chloride gas orhydrochloric acid.

According to another route (Scheme 2), the phenol 10 is subjected to anO-alkylation with bromoacetaldehyde diethyl ether via phase-transfercatalysis in the presence of base such as potassium carbonate to givethe alkylated compound 11. The phase-transfer catalysts could be used inthis reaction includes 18-crown-6, tetrabutylammonium hydrogen sulfate,tetrabutylammonium bromide and the like. The arylidene compound 13 canbe prepared, as described in Scheme 1, by substitution of the mercaptocompound 12 with amines R₆H. In some cases, however, compound 13 couldbe made directly from the Knoevenagel condensation between intermediate11, lactams and amines R₆H. Ketal hydrolysis followed by reductiveamination, as previously described in Scheme 1, furnishes the finalproduct, wherein A, R₁, R₂, R₃, R₄, R₅, R₆, X and Z are as definedabove. A salt is optionally produced by the addition of an acid or base,such as hydrogen chloride gas or hydrochloric acid.

Many of arylethanolamines or aryloxypropanolamines 8 are commerciallyavailable or readily prepared by known methods [1. Guy, A., Ferroud, D.C., Garreay, R., Godefroy-Falguieres A. Synthesis, 1992, 821; 2.Leclerc, G., Bizec, J. C. J. Med. Chem., 1980, 23, 738; 3. Tominaga, M.,Ogawa, H., Yo, E., Yamashita, S., Yabuuchi, Y., Nakagawa, K. Chem.Pharm. Bull. 1987, 35, 3699]. In one route (Scheme 3) equimolecularamounts of alcohol 16 and enantiomerically pure (2S)-glycidyl3-nitrobenzene sulfonate 17 are dissolved in an organic solvent such asacetone or dimethylformamide and treated with a base such as sodiumhydride or potassium carbonate for 0.5 to 24 hours at a temperature of20-100° C. to provide oxirane 18. The oxirane 18 is converted to thecorresponding amine 20 or 22, wherein A, R₁, R₂, and R₃ are as definedabove (provided that in 22 R₁, R₂, and R₃ can not be benzyloxy), byregioselective ring opening of oxirane 18 with either lithium azide in asolvent such as hexamethylphosphoramide followed by reduction with, forexample, triphenylphosphine in aqueous tetrahydrofuran, or with oneequivalent of dibenzylamine followed by ammonium formate/palladium oncarbon reduction. The other enantiomer is available through an analogouspreparative sequence with the corresponding (2R)-glycidyl 3-nitrobenzenesulfonate.

One route to the desired arylethanolamines 8 is illustrated in Scheme 4.Methylketones 23 are all available commercially or can be prepared byconventional methods disclosed in the art. Compound 23 can be easilyconverted to the corresponding α-haloketone 24, wherein halo ischlorine, bromine or iodine, using well known halogenation agents suchas chlorine, bromine, N-chlorosuccinimide, N-bromosuccinimide and thelike. The resultant (α-haloketone 24 is then reduced, for example, bysodium borohydride, to give the corresponding racemic alcohol 25. Anenantiomerically enriched alcohol 25 may be prepared by asymmetricreduction of α-haloketone 24 with chiral reducing agents such as (+) or(−)-B-chlorodiisopinocampheylborane (DIP-CI), R or S-Alpine borane,cis-(1R, 2S) or cis (1S, 2R)-oxazaborolidine and the like. The alcoholof intermediate 25 may be protected, for example, as its triethylsilylether. In some cases, however, the alcohol protecting group is notrequired. The halo compound 25 can be easily converted to thecorresponding benzylamine 26 by heating to 30-80° C. with a large excessof benzylamine neat or as a solution in a polar solvent such astetrahydrofuran, acetonitrile or methanol for 1 to 24 hours. Theprotecting group is then removed, in the case of silyl ether, bytreatment of 26 with a fluoride agent such as tetrabutylammoniumfluoride. Compound 27 is then subjected to catalytic hydrogenation inthe presence of ammonium formate/palladium on carbon to give the desiredaminoethanol 28, wherein A, R₁, R₂ and R₃ are as defined above. Thereduction is conveniently conducted in refluxing methanol in thepresence of a large excess of ammonium formate.

Alternatively, the chloride 25 could be converted to the correspondingamine 28 by treatment with a sodium azide/sodium iodide mixture in apolar solvent such as dimethyl sulfoxide, hexamethylphosphoramide andthe like followed by catalytic hydrogenation in the presence of a metalcatalyst such as palladium, platinum and the like.

The compounds of this invention are useful in treating metabolicdisorders related to insulin resistance or hyperglycemia, typicallyassociated with obesity or glucose intolerance. The compounds of thisinvention are therefore, particularly useful in the treatment orinhibition of type II diabetes. The compounds of this invention are alsouseful in modulating glucose levels in disorders such as type Idiabetes.

The ability of compounds of this invention to treat or inhibit disordersrelated to insulin resistance or hyperglycemia was established withrepresentative compounds of this invention in the following standardpharmacological test procedures, which measured the binding selectivityto the β₁, β₂, and β₃ adrenergic receptors. Binding to the receptors wasmeasured in Chinese Hamster ovary (CHO) cells that were transfected withadrenergic receptors. The following briefly summarizes the proceduresused and results obtained.

Transfection of CHO cells with β₁ and β₂ adrenergic receptors: CHO cellswere transfected with human β₁- or β₂-adrenergic receptors as describedin Tate, K. M.,, Eur. J. Biochem., 196:357-361 (1991).

Cloning of Human β₃-AR Genomic DNA: CDNA was constructed by ligatingfour polymerase chain reaction (PCR) products using the followingprimers: an ATG-Narl fragment, sense primer5′-CTTCCCTACCGCCCCACGCGCGATC3′, and anti-sense primer5′CTGGCGCCCAACGGCCAGTGGCCAGTC3′; a Narl-Accl fragment,5′TTGGCGCTGATGGCCACTGGCCGTTTG3′ as sense and5′GCGCGTAGACGAAGAGCATCACGAG3′ as anti-sense primer; an Accli-Stylfragment, sense primer 5′CTCGTGATGCTCTTCGTCTCACGCGC3′ and anti-senseprimer 5′GTGAAGGTGCCCATGATGAGACCCAAGG3′ and a Styl-TAG fragment, withsense primer 5′CCCTGTGCACCTTGGGTCTCATCATGG3′ and anti-sense primer5′CCTCTGCCCCGGTTACCTACCC3′. The corresponding primer sequences aredescribed in Mantzoros, C. S., et.al., Diabetes 45: 909-914 (1996). Thefour fragments are ligated into a pUC 18 plasmid (Gibco-BRL) andsequenced. Full length β₃ AR clones (402 amino acids) containing thelast 6 amino acids of hβ₃-AR are prepared with the β₃-βARpcDNA3 fromATTC.

Binding Procedure: Clones expressing receptor levels of 70 to 110fmoles/mg protein were used in the test procedures. CHO cells were grownin 24-well tissue culture plates in Dulbecco's Modified Eagle Media with10% fetal bovine serum, MEM non-essential amino acids,Penicillin-Streptompycin and Geneticin. On the day of test procedure,growth medium was replaced with preincubation media (Dulbecco's ModifiedEagle Media) and incubated for 30 minutes at 37° C. Preincubation mediumwas replaced with 0.2 ml treatment medium containing DMEM mediacontaining 250 μM IBMX (isobutyl-1-methylxantine) plus 1 mM ascorbicacid with test compound dissolved in DMSO. Test compounds were testedover a concentration range of 10⁻⁹ M to 10⁻⁵ M for β₃ cells and 10⁻⁸ to10⁻⁴ M for β₁ and β₂ transfected cells. Isoproterenol (10⁻⁵ M) was usedas an internal standard for comparison of activity. Cells were incubatedat 37° C. on a rocker for 30 min with the β₃ cells and 15 min for β₁ andβ₂ cells. Incubation was stopped with the addition of 0.2N HCl andneutralized with 2.5N NaOH. The plates, containing the cells andneutralized media, were stored at −20 degrees celsius until ready totest for cAMP using the SPA test kit (Amersham).

Data Analysis and Results: Data collected from the SPA test procedurewere analyzed as per cent of the maximal isoproterenol response at 10⁻⁵M. Activity curves were plotted using the SAS statistical and graphicssoftware. EC₅₀ values were generated for each compound and the maximalresponse (IA) developed for each compound is compared to the maximalresponse of isoproternol at 10⁻⁵ M from the following formula:${IA} = \frac{\% \quad {activity}\quad {compound}}{\% \quad {activity}\quad {isoproterenol}}$

Table I shows the β₃-adronergic receptor EC₅₀ and IA values for therepresentative compounds of this invention that were evaluated in thisstandard pharmacological test procedure. These results show thatcompounds of the present invention have activity at the β₃-adrenergicreceptor. The compounds of this invention had weaker or no activity atβ₁ and/or β₂-adrenergic receptor.

TABLE I Compound No. EC₅₀(β₃, nM) IA(β₃) Example 1 9 1.0 Example 2 221.0 Example 3 30 0.52 Example 4 230 0.6 Example 5 9 1.22 Example 6 100.94 Example 7 9 1.06 Example 8 8 0.75 Example 9 7 0.81 Example 10 190.69 Example 11 8 0.83 Example 12 9 0.95 Example 13 3 0.86 Example 14 11.0 Example 15 6 1.1 Example 16 75 0.96 Example 17 2 1.0 Example 18 30.89 Example 20 937 0.79 Example 21 400 0.93 Example 22 40 0.58 Example23 76 0.78 Example 24 1920 1.0 Example 25 450 0.51 Example 26 156 0.85Example 27 0.58 Example 28 1 1.1 Example 29 17 0.91 Example 30 1 1.0Example 31 210 0.84 Example 32 88 0.33 Example 33 2 0.86 Example 34 31.0

Based on the results obtained in these standard pharmacological testprocedures, representative compounds of this invention have been shownto be selective β₃ adrenergic receptor agonists and are therefore usefulin treating metabolic disorders related to insulin resistance orhyperglycemia (typically associated with obesity or glucoseintolerance), atherosclerosis, gastrointestinal disorders, neurogeneticinflammation, and frequent urination; and are particularly useful in thetreatment or inhibition of type II diabetes, and in modulating glucoselevels in disorders such as type I diabetes. As used herein, the termmodulating means maintaining glucose levels within clinically normalranges.

As used in accordance with this invention, the term providing aneffective amount means either directly administering such a compound ofthis invention, or administering a prodrug, derivative, or analog whichwill form an effective amount of the compound of this invention withinthe body.

It is understood that the effective dosage of the active compounds ofthis invention may vary depending upon the particular compound utilized,the mode of administration, the condition, and severity thereof, of thecondition being treated, as well as the various physical factors relatedto the individual being treated. As used in accordance with invention,satisfactory results may be obtained when the compounds of thisinvention are administered to the individual in need at a daily dosageof from about 0.1 mg to about 1 mg per kilogram of body weight,preferably administered in divided doses two to six times per day, or ina sustained release form. For most large mammals, the total daily dosageis from about 3.5 mg to about 140 mg. It is preferred that theadministration of one or more of the compounds herein begin at a lowdose and be increased until the desired effects are achieved.

Such doses may be administered in any manner useful in directing theactive compounds herein to the recipient's bloodstream, includingorally, via implants, parenterally (including intravenous,intraperitoneal and subcutaneous injections), rectally, intranasally,vaginally, and transdermally. For the purposes of this disclosure,transdermal administrations are understood to include alladministrations across the surface of the body and the inner linings ofbodily passages including epithelial and mucosal tissues. Suchadministrations may be carried out using the present compounds, orpharmaceutically acceptable salts thereof, in lotions, creams, foams,patches, suspensions, solutions, and suppositories (rectal and vaginal).

Oral formulations containing the active compounds of this invention maycomprise any conventionally used oral forms, including tablets,capsules, buccal forms, troches, lozenges and oral liquids, suspensionsor solutions. Capsules may contain mixtures of the active compound(s)with inert fillers and/or diluents such as the pharmaceuticallyacceptable starches (e.g. corn, potato or tapioca starch), sugars,artificial sweetening agents, powdered celluloses, such as crystallineand microcrystalline celluloses, flours, gelatins, gums, etc. Usefultablet formulations may be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants,suspending or stabilizing agents, including, but not limited to,magnesium stearate, stearic acid, talc, sodium lauryl sulfate,microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, , xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations herein may utilize standard delay or timerelease formulations to alter the absorption of the active compound(s).

In some cases it may be desirable to administer the compounds directlyto the airways in the form of an aerosol.

The compounds of this invention may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxy-propylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparation contain a preservative to prevent thegrowth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin. Water soluble suppositorybases, such as polyethylene glycols of various molecular weights, mayalso be used.

The compounds of the present invention also possess utility forincreasing lean meat deposition and/or improving lean meat to fat ratioin edible animals, i.e. ungulate animals and poultry.

Animal feed compositions effective for increasing lean meat depositionand for improving lean meat to fat ratio in poultry, swine, sheep,goats, and cattle are generally prepared by mixing the compounds of thepresent invention with a sufficient amount of animal feed to providefrom about 1 to 1000 ppm of the compound in the feed. Animal feedsupplements can be prepared by admixing about 75% to 95% by weight of acompound of the present invention with about 5% to about 25% by weightof a suitable carrier or diluent. Carriers suitable for use to make upthe feed supplement compositions include the following: alfalfa meal,soybean meal, cottonseed oil meal, linseed oil meal, sodium chloride,cornmeal, cane molasses, urea, bone meal, corncob meal and the like. Thecarrier promotes a uniform distribution of the active ingredients in thefinished feed into which the supplement is blended. It thus performs animportant function by ensuring proper distribution of the activeingredient throughout the feed. The supplement is used as a top dressingfor the feed, it likewise helps to ensure uniformity of distribution ofthe active material across the top of the dressed feed.

The preferred medicated swine, cattle, sheep and goat feed generallycontain from 0.01 to 400 grams of active ingredient per ton of feed, theoptimum amount for these animals usually being about 50 to 300 grams perton of feed. The preferred poultry and domestic pet feed usually containabout 0.01 to 400 grams and preferably 10 to 400 grams of activeingredient per ton of feed.

For parenteral administration the compounds of the present invention maybe prepared in the form of a paste or a pellet and administered as animplant, usually under the skin of the head or ear of the animal inwhich increase in lean meat deposition and improvement in lean mean tofat ratio is sought. In general, parenteral administration involvesinjection of a sufficient amount of the compounds of the presentinvention to provide the animal with 0.001 to 100 mg/kg/day of bodyweight of the active ingredient. The preferred dosage for swine, cattle,sheep and goats is in the range of from 0.001 to 50 mg/kg/day of bodyweight of active ingredient; whereas, the preferred dose level forpoultry and domestic pets is usually in the range of from 0.001 to 35mg/kg/day of body weight.

Paste formulations can be prepared by dispersing the active compounds ina pharmaceutically acceptable oil such as peanut oil, sesame oil, cornoil or the like. Pellets containing an effective amount of the compoundsof the present invention can be prepared by admixing the compounds ofthe present invention with a diluent such as carbowax, carnuba wax, andthe like, and a lubricant, such as magnesium or calcium stearate, can beadded to improve the pelleting process. It is, of course, recognizedthat more than one pellet may be administered to an animal to achievethe desired dose level which will provide the increase in lean meatdeposition and improvement in lean meat to fat ratio desired. Moreover,it has been found that implants may also be made periodically during theanimal treatment period in order to maintain the proper drug level inthe animal's body. For the poultry and swine raisers, using the methodof the present invention yields leaner animals.

Additionally, the compounds of this invention are useful in increasingthe lean mass to fat ratio in domestic pets, for the pet owner orveterinarian who wishes to increase leanness and trim unwanted fat frompet animals, the present invention provides the means by which this canbe accomplished.

The following procedures describe the preparation of intermediatesuseful in the preparation of compounds of this invention.

Intermediate 1

(1R)-2-Amino-1-(3-chloro-phenyl)-ethanol:

Lithium azide (7.5 g, 150 mmol) was added to a solution of(1R)-1-(3-chloro-phenyl)oxirane (15.5 g, 100 mmol) inhexamethylphosphoramide (70 mL). After being stirred at room temperaturefor 16 hours the suspension was poured into ice-water and the mixturewas extracted with diethyl ether. The combined extracts were dried overmagnesium sulfate and concentrated. The residue was dissolved in 550 mLof tetrahydrofuran/water (10:1) and triphenylphosphine (30 g, 114 mmol)was added. After overnight stirring at room temperature, the solventswere removed and the residue was purified by column chromatography onsilica gel using triethylamine-methanol-methylene chloride (1:1:8) asthe eluent to give the title compound as a free base.

The title compound was characterized as its hydrochloric salt: The freebase from above was then dissolved in diethyl ether and slowly treatedwith hydrogen chloride gas. The precipitate was collected by filtrationto yield 15 g (72%) of the title compound as a white powder; ¹H NMR (300MHz, DMSO-d₆) δ 2.83 (dd, J=12.8, 9.5 Hz, 1 H), 3.06 (dd, J=12.8, 3.2Hz, 1 H), 4.80-4.90 (m, 1 H), 6.22 (d, J=4.0 Hz, 1 H), 7.10-7.75 (m, 4H), 8.08 (brs, 2 H ); MS (ES) m/z: 171.7, 173.7 (MH⁺); HRMS Calcd. forC₈H₁₀CINO(MH⁺): 172.0529. Found: 172.0531.

Intermediate 2

(2S)-2-Phenoxymethyl-oxirane:

A solution of phenol (9.4 g, 100 mmol) and (2S)-(+)glycidyl3-nitrobenzesulfonate(25.9 g, 100 mmol) in 500 mL of acetone was treatedwith 3 equivalents of potassium carbonate (41.5 g, 300 mmol) and stirredat reflux for 1 day. The suspension was cooled to ambient temperature;the solid was filtered; and the filtrate concentrated to dryness. Theresidue was partitioned between methylene chloride and water and theaqueous layer was extracted with methylene chloride. The organic layerswere combined and dried over magnesium sulfate and concentrated to givethe title compound (15.0 g, 99%) as an orange oil; ¹H NMR (300 MHz,CDCl₃) δ 6 2.76 (dd, J=4.9, 2.6 Hz, 1 H), 2.90 (dd, J=4.9, 4.9 Hz, 1 H),3.30-3.40 (m, 1 H), 3.95 (dd, J=11.0, 5.4 Hz, 1 H), 4.18 (dd, J=11.0,3.0 Hz, 1 H), 6.85-7.00 (m, 3 H), 7.25-7.35 (m, 2 H); MS (ES) m/z: 151.0(MH⁺).

Intermediate 3

(2S)-1-Amino-3-phenoxypropan-2-ol:

The title compound was prepared from (2S)-2-phenoxymethyl-oxirane (whichwas obtained in Intermediate 2) according to the procedure ofIntermediate 1 as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 2.56 (dd,J=12.8, 6.3 Hz, 1 H), 2.67 (dd, J=12.8, 4.9 Hz, 1 H), 3.65-3.75 (m, 1H), 3.82 (dd, J=9.8, 6.0 Hz, 1 H), 3.93 (dd, J=9.8, 5.0 Hz, 1 H),6.85-6.95 (m, 3 H), 7.20-7.30 (m, 2 H); MS (ES) m/z: 167.7 (MH⁺); HRMSCalcd. for C₉H₁₃NO₂(M⁺): 167.0946. Found: 167.0945.

Intermediate 4

(2S)-1-Amino-3-(4-benzyloxy-phenoxy)-propan-2-ol:

The title compound was prepared from(2S)-2-(4-benzyloxy-phenoxymethyl-oxirane (Sher, P. M., et al., EP 0 714883) according to the procedure of Intermediate 1 as a white solid; ¹HNMR (300 MHz, CDCl₃) δ 2.50-2.70 (m, 2 H), 3.33 (brs, 2 H), 3.60-3.90(m, 3 H), 5.02 (s, 2 H), 6.90 (d, J=6.7 Hz, 2 H), 6.93 (d,J=6.7 Hz, 2H), 7.25-7.50 (m, 5 H); MS (ES) m/z: 274.1 (MH⁺); HRMS Calcd. forC₁₆H₁₉NO₃(M⁺): 273.1365. Found: 273.1347. Anal. Calcd. for C₁₆H₁₉NO₃: C,70.31; H, 7.01; N, 5.12. Found: C, 70.39; H, 6.80; N, 5.23.

Intermediate 5

(2S)-1-Amino-3-(4-hydroxy-phenoxy)-propan-2-ol:

A mixture of (2S)-1-amino-3-(4-benzyloxy-phenoxy)-propan-2-ol (which wasobtained in Intermediate 4) (0.9 g, 3.3 mmol), 0.2 mL of acetic acid and10% palladium on carbon (0.3 g) in 70 mL of ethanol was pressurized with20 psi hydrogen and shaken over 2 hours. The catalyst was then removedby filtering through a short pad of silica gel and the solvent wasremoved to give the title compound as an off-white solid; ¹H NMR (300MHz, DMSO-d₆) δ 1.86 (s, 1 H), 2.66 (dd, J=12.8, 5.3 Hz, 1H), 2.85 (dd,J=12.8, 3.5 Hz, 1H), 3.79-3.95 (m, 3 H), 6.67 (d, J=6.6 Hz, 2H), 6.75(d, J=6.6 Hz, 2 H); MS (ES) m/z: 183.1 (MH⁺); HRMS Calcd. forC₉H₁₃NO₃(MH⁺): 183.0895. Found: 183.0892.

Intermediate 6

N-[2-Benzyloxy-5-(2-dibenzylamino-1-oxo-ethyl)-phenyl]-methanesulfonamide:

N-[2-Benzyloxy-5-(2-chloro-1-oxo-ethyl)-phenyl]-methanesulfonamide(Washburn, W. N., et al., EP 0 659 737) (17.0 g, 42.8 mmol) wasdissolved in 200 mL of dimethylformamide and treated with dibenzylamine(22.0 g, 110 mmol). The mixture was stirred at room temperatureovernight and then the solvent was removed. The residue was purified bysilica gel chromatography using 20-50% ethyl acetate/hexanes as eluentto give the title compound as a white solid; ¹H NMR (300 MHz, CDCl₃) δ2.94 (s, 3 H), 3.77 (s, 2 H), 3.82 (s, 2 H), 5.16 (s, 2 H), 6.75 (brs, 1H), 6.96 (d, J=8.7 Hz, 1 H), 7.20-7.50 (m, 15 H), 7.67 (dd, J=8.7, 2.1Hz, 1 H), 8.10 (d, J=2.1 Hz, 1 H); MS (ES) m/z: 515.2 (MH⁺); HRMS Calcd.for C₃₀H₃₀N₂O₄S(M^(30 ):) 514.1926. Found: 514.1927.

Intermediate 7

N-[2-Benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide:

Sodium borohydride (0.37 g, 9.7 mmol) was added in portions to a stirredsolution ofN-[2-benzyloxy-5-(2-dibenzylamino-1-oxo-ethyl)-phenyl]-methanesulfonamide(which was obtained in Intermediate 6) (1.0 g, 1.9 mmol) in 20 mL ofmethanol/tetrahydrofuran (5:2) at room temperature and the resultingsolution was stirred for 2 hours. Methylene chloride was added and theresulting solution was washed with aqueous sodium bicarbonate, driedover magnesium sulfate and the solvents were removed. Recrystallizationfrom methylene chloride/hexanes gave the title compound as a crystallinesolid; ¹H NMR (300 MHz, CDCl₃) δ 2.58 (d, J=6.7 Hz, 2 H), 2.86 (s, 2 H),2.92 (s, 2 H), 3.55 (d, J=13.5 Hz, 2 H), 3.70 (d, J=13.5 Hz, 2 H), 4.11(s, 1 H), 4.64 (t, J=6.7 Hz, 1 H), 5.10 (s, 2 H), 6.92 (d, J=8.5 Hz, 1H), 7.00 (dd, J=8.5, 2.0 Hz, 1 H), 7.20-7.50 (m, 16 H), 7.89 (brs, 1 H);MS (ES) m/z: 517.1 (MH⁺); HRMS Calcd. for C₃₀H₃₂N₂O₄S(M⁺): 516.2083.Found: 516.2074.

Intermediate 8

N-[5-((1R)-2-Azido-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-methanesulfonamide:

To a stirred solution ofN-[2-benzyloxy-5-(2-bromo-1-hydroxy-ethyl)-phenyl]-methanesulfonamide(Washburn, W. N., et al., EP 0 659 737) (15.05 g, 38 mmol) in dimethylsulfoxide (150 ml) was added sodium iodide (3.76 g, 376 mmol) and sodiumazide (9.48 g, 150 mmol). The mixture was stirred for 5 days undernitrogen atmosphere. The reaction mixture was poured onto water andextracted three times with ethyl acetate. The combined organic layerswere dried over sodium sulfate and concentrated. The residue wastriturated with water and hexanes to give the title compound as a yellowsolid (12.85 g, 94%): ¹H NMR (300 MHz, CDCl₃) δ 2.93(s, 3 H), 3.47(d,J=5.4 Hz, 2 H), 4.84(t, J=5.4 Hz, 1 H), 5.11(s, 2 H), 6.80(s, 1 H),6.99(d, J=8.4 Hz, 1 H), 7.15(dd, J=8.4 Hz, 2.1 Hz, 1H), 7.26(s, 1 H),7.30-5.50(m, 5 H), 7.53(d, J=2.1 Hz, 1 H); MS (ES) m/z 361.4 ((M-H)-,70%).

Intermediate 9

N-[5-(2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide:

To a stirred suspension ofN-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide(which was obtained in Intermediate 7)(1.03g, 2 mmol) and 10% palladiumon carbon (0.4 g) in methanol (100 mL) at room temperature was addedanhydrous ammonium formate (1.26 g, 20 mmol) under a nitrogenatmosphere. The resulting mixture was refluxed for 2 hours. Aftercooling to room temperature the catalyst was removed by filtrationthrough a celite pad and washed with methanol. The filtrate wasevaporated under reduced pressure to give the titled compound (Leclerc,G., Bizec, J. C. J. Med. Chem., 1980, 23, 738) as a pale yellowishsolid; ¹H NMR (300 MHz, DMSO-d₆) δ 2.62 (dd, J=12.6, 8.7 Hz, 1 H), 2.75(dd, J=12.6, 3.7 Hz, 1 H), 2.90 (s, 3 H), 4.47 (dd, J=8.7, 3.7 Hz, 1 H),6.84 (d, J=9.1 Hz, 1 H), 6.96 (dd, J=9.1, 2.0 Hz, 1 H), 7.16 (d, J=2.1Hz, 1 H), 8.44 (s, 1 H); MS (ES) m/z: 246.7 (MH⁺); HRMS Calcd. forC₉H₁₄N₂O₄S(M⁺): 246.0674. Found: 246.0672.

Intermediate 10

N-[5-(2-Amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide:

Method A: A mixture ofN-{2-benzyloxy-5-(2-iodo-(1R)-1-[(triethylsilyl)oxy]-ethyl)-phenyl}-methanesulfonamide(Washburn, W. N., et al., EP 0 659 737) (8.60 g, 15.3 mmol) andbenzylamine (21.4 g, 200 mmol) was heated at 60° C. for 24 hours. Thereaction mixture was cooled, diluted with hexanes (500 mL), and theresidue was washed with diethyl ether. The combined solvents wereremoved and the residue was purified by silica gel column eluting with30 to 100% diethyl ether/hexanes. The fractions with molecular weight of540 were concentrated and re-dissolved in 200 mL of tetrahydrofuran andtetrabutylammonium fluoride (20 mL, 1.0 M solution in tetrahydrofuran)was added. After stirring at room temperature for 4 hours the reactionmixture was then poured into water and extracted with methylenechloride. The organic layers were passed through a short pad of silicagel eluting with 10% methanol/methylene chloride. The solvents wereremoved and the residue was dissolved in methanol (200 mL). 10%Palladium on carbon (0.6 g) and anhydrous ammonium formate (6.3 g, 100mmol) were added. The resulting mixture was refluxed under a nitrogenatmosphere for 2 hours. After cooling to room temperature the catalystwas removed by filtration through a celite pad and washed with methanol.The filtrate was evaporated under reduced pressure to give the titlecompound as an off-white solid; ¹H NMR (300 MHz, MeOH-d⁴) δ 2.95 (s, 3H), 2.99 (dd, J=9.7, 9.2 Hz, 1 H), 3.07 (dd, J=9.7, 3.6 Hz, 1 H), 4.75(dd, J=9.2, 3.6 Hz, 1 H), 6.90 (d, J=8.3 Hz, 1 H), 7.12 (dd, J=8.3, 2.1Hz, 1 H), 7.38 (d, J=2.1 Hz, 1 H), 8.44 (s, 1 H); MS (ES) m/z: 246.7(MH⁺); HRMS Calcd. for C₉H₁₄N₂O₄S(M⁺): 246.0674. Found: 246.0672. MethodB: A mixture ofN-[5-((1R)-2-azido-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-methanesulfonamide(which was obtained in Intermediate 8)(12.85 g, 0.037 mol) and 10%palladium on carbon (2.75 g) in ethanol (100 ml) was hydrogenated under45 psi for two days. The reaction mixture was filtered through celiteand concentrated. The title compound was recovered as an off-white solid(6.08 g, 66%).

Intermediate 11

8-Benzyloxy-(5S)-5-oxiranylmethoxy-3,4-dihydro-1H-quinolin-2-one:

The title compound was prepared from8-benzyloxy-5-hydroxy-3,4-dihydro-1H-quinolin-2-one (Tominaga, M.,Ogawa, H., Yo, E., Yamashita, S., Yabuuchi, Y., Nakagawa, K. Chem.Pharm. Bull. 1987, 35, 3699) according to the procedure of Intermediate2; ¹H NMR (300 MHz, DMSO-d₆) δ 2.41 (t, J=7.1 Hz, 2 H), 2.69 (dd, J=5.1,2.7 Hz, 1 H), 2.75-2.86 (m, 4 H), 3.78 (dd, J=11.4, 6.3 Hz, 1 H), 4.23(dd, J=11.4, 2.6 Hz, 1 H), 5.09 (s, 2 H), 6.54 (d, J=9.0 Hz, 2 H), 6.86(d, J=9.0 Hz, 2 H), 7.25-7.45 (m, 3 H), 7.51 (d, J=8.2 Hz, 2 H), 9.08(s, 1 H); MS (ES) m/z: 326.0 (MH⁺); HRMS Calcd. for C₁₉H₂₀NO₄(MH⁺):326.1392. Found: 326.1343. Anal. Calcd. for C₁₉H₁₉NO₄: C, 70.14; H,5.89; N, 4.30. Found: C, 70.14; H, 5.69; N, 4.20.

Intermediate 12

5-(3-Amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one:

Dibenzylamine (1.46g, 7.4 mmol) was added to a stirred solution of8-benzyloxy-(5S)-5-oxiranylmethoxy-3,4-dihydro-1H-quinolin-2-one(whichwas obtained in Intermediate 11) (2.0 g, 6.2 mmol) in 100 mL ofmethanol. After refluxing overnight the mixture was cooled down to roomtemperature and 10% palladium on carbon (0.5 g) and ammonium formate(3.15 g, 50 mmol) were added. The suspension was refluxed for anotherhour. After cooling the suspension the reaction mixture was filteredthrough celite. The filtrate was concentrated to give the title compoundas a pale grey solid; ¹H NMR (300 MHz, DMSO-d₆) δ 2.42(t, J=7.1 Hz, 2H), 2.74 (dd, J=12.8, 8.2 Hz, 1 H), 2.81 (t, J=7.0 Hz, 2 H), 2.95 (dd,J=12.8, 3.4 Hz, 1 H), 3.65-3.95 (m, 3 H), 6.45 (d, J=8.8 Hz, 2 H), 6.62(d, J=8.8 Hz, 2 H), 8.38 (s, 1 H), 8.77 (brs, 1 H); MS (ES) m/z: 252.9(MH⁺); HRMS Calcd. for C₁₂H₁₆N₂O₄(M⁺): 252.1188. Found: 252.1199.

Intermediate 13

N-Benzyl-N-(2-benzyloxy-5-oxiranylmethoxy-phenyl)-methanesulfonamide:

The title compound was prepared fromN-benzyl-N-(2-benzoxy-5-hydro-phenyl)-methanesulfonamide(Kaiser, C.;Jen, T.; Garvey, E.; and Bowen, W. D. J. Med. Chem. 1977, 20, 687)according to the procedure of Intermediate 2 as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 2.63(dd, J=5.1, 2.6 Hz, 1 H), 2.80(t, J=4.9 Hz, 1H), 3.10-3.20(m, 1 H), 3.66(dd, J=11.4, 6.6 Hz, 1 H), 4.16(dd, J=11.4,2.6 Hz, 1 H), 4.73(brs, 2 H), 5.12(s, 2 H), 6.69 (d, J=3.1 Hz, 1 H),6.88(dd, J=9.1, 3.1 Hz, 1 H), 7.08 (d, J=9.1 Hz, 1 H), 7.15-7.60(m, 10H); MS (ES) m/z:439.9 (MH⁺, 100%); HRMS Calcd. for C₂₄H₂₅NO₅S (M+):439.1454. Found: 439.1457.

Intermediate 14

N-[5-((2S)-3-Amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide:

The title compound was prepared fromN-benzyl-N-(2-benzyloxy-5-oxiranylmethoxy-phenyl)-methanesulfonamide(whichwas obtained in Intermediate 13) according to the procedure ofIntermediate 12 as a pale grey solid; ¹H NMR (300 MHz, DMSO-d₆) δ2.61(dd, J=12.7, 6.1 Hz, 1 H), 2.75(dd, J=12.7, 3.5 Hz, 1 H), 2.86(s, 3H), 3.69-3.90(m, 3 H), 6.55(dd, J=8.7, 3.1 Hz, 1 H), 6.70(d, J=8.7 H),6.75 (d, J=3.1 Hz, 1 H); MS (ES) m/z: 276.8 (MH⁺, 100%); HRMS Calcd. forC₁₀H₁₆N₂O₅S (M+): 276.0780. Found: 276.0792.

Intermediate 15

5-[4(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-thioxothiazolidin-4-one:

A mixture of 4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzaldehyde(Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) (4.96 g, 20 mol),rhodanine (2.66 g, 20 mmol), and β-alanine (2.0 g, 22.5 mmol) in 50 mLof acetic acid was refluxed for 2 hours. The solid which was formed oncooling the solution was collected to give the title compound as a redsolid (4.8 g, 66%); ¹H NMR (300 MHz, CDCl₃) δ 1.81 (t, J=5.5 Hz, 4 H),3.55 (t, J=5.5 Hz, 4 H), 4.00 (s, 4 H), 6.92 (d, J=8.9 Hz, 2 H), 7.58(d, J=8.9 Hz, 2 H), 7.38 (s, 1 H); MS (ES) m/z: 362.8 (MH⁺); HRMS Calcd.for C₁₇H₁₉N₂O₃S₂(MH^(+):) 363.0837. Found: 363.0852. Anal. Calcd. forC₁₇H₁₈N₂O₃S₂: C, 56.33; H, 5.01; N, 7.73. Found: C, 56.28; H, 4.89; N,7.73.

Intermediate 16

5-[4-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one:

A mixture of5-[4(1,4-dioxa-8-aza-spiro[4,5]dec-6-yl)-benzylidene]-2-thioxothiazolidin-4-one(whichwas obtained in Intermediate 15) (1.50 g, 4.14 mmol),N,N-diisopropylethylamine (0.65 g, 5 mmol), iodomethane (1.13 g, 8 mmol)in ethanol (50 mL) was stirred at room temperature overnight. Water (300mL) was then added and the mixture was stirred for another hour. Thesolid which was formed was collected and dried to give the titlecompound as a red solid; ¹H NMR (300 MHz, CDCl₃) δ 1.80 (t, J=5.8 Hz, 4H), 2.88 (s, 3 H), 3.50 (t, J=5.8 Hz, 4 H), 4.00 (s, 4 H), 6.90 (d,J=9.0 Hz, 2 H), 7.45 (d, J=9.0 Hz, 2 H), 7.80 (s, 1 H); MS (ES) m/z:376.9 (MH⁺, 100%), 752.9 ((2M+H)^(+,) 5%); HRMS Calcd. for C₁₈H₂₀N₂O₃S₂(M^(+):) 376.0915. Found: 376.0888. Anal. Calcd. for C₁₈H₂₀N²O₃S₂: C,57.42; H, 5.35; N, 7.44. Found: C, 57.34; H, 5.18; N, 7.34.

Intermediate 17

5-[4-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylamino-thiazo-4-one:

A mixture of5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(whichwas obtained in Intermediate 16) (0.56 g, 1.5 mmol) and methylamine (7.5mL, 2.0 M solution in tetrahydrofuran) in ethanol (100 mL) was refluxedovernight. After cooling to room temperature hexanes (70 mL) was addedand the solid which was formed was collected to give the title compoundas a yellowish solid (olefinic cis/trans mixture, ratio 3 to 1); ¹H NMR(300 MHz, CDCl₃) δ 1.75-1.85 (m, 4 H), 3.19 (s, 3 H), 3.40-3.50 (m, 4H), 4.00(s, 4 H), 6.98 (d, J=9.0 Hz, 2 H), 7.46 (d, J=9.0 Hz, 2 H), 7.71(s, 1 H); MS (ES) m/z: 359.9 (MH⁺, 100%), 719.0 ((2M+H)⁺, 10%); HRMSCalcd. for C₁₈H₂₁N₃O₃S (M⁺): 359.1304. Found: 359.1307.

Intermediate 18

1-[4-(2-Methylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperdin-4-one:

5-[4-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylamino-thiazo-4-one(whichwas obtained in Intermediate 17) (0.25 g, 0.7 mmol) was treated withconcentrated hydrochloric acid (18 mL) at room temperature. After 30minutes the solution was neutralized with ˜28% ammonium hydroxide andthe precipitate was collected by filtration, and dried to give the titlecompound as a yellowish solid (0.20g, 91%, olefinic cis/trans mixture,ratio 5 to 1); ¹H NMR (300 MHz, DMSO-d₆) δ 2.43 (t, J=5.9Hz, 4 H), 3.05(s, 3 H), 3.73 (t, J=5.9Hz, 4 H), 7.13 (d, J=7.3 Hz, 2 H), 7.46 (d,J=7.3 Hz, 2 H), 7.50 (s, 1 H), 9.41 (brs, 1 H); MS (ES) m/z: 315.8 (MH⁺,100%), 631.0 ((2M+H)⁺, 10%); HRMS Calcd. for C₁₆H₁₇N₃O₂S (M⁺): 315.1041.Found: 315.1057.

Intermediate 19

5-[4-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-(2-morpholin-4-yl-ethylamino)-thiazo-4-one:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(whichwas obtained in Intermediate 16) and 4-(2-aminoethyl) morpholineaccording to the procedure of Intermediate 17 as a yellowish solid (onemajor isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 1.68 (t, J=5.5 Hz, 4 H),2.35-2.55 (m, 6 H), 3.44 (t, J=5.5 Hz, 4 H), 3.55-3.65 (m, 6 H), 3.92(s,4 H), 7.07 (d, J=8.9 Hz, 2 H), 7.40 (d, J=8.9 Hz, 2 H), 7.47 (s, 1 H),9.43 (brs, 1 H); MS (ES) m/z: 229.9 ((M+2H)²⁺, 40%), 458.9 (MH⁺, 100%),917.2 ((2M+H)⁺, 3%); HRMS Calcd. for C₂₃H₃₀N₄O₄S (M⁺): 458.1988. Found:458.1979.

Intermediate 20

1-{4-[2-(2-Morpholin-4-yl-ethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl-benzylidene]-2-(2-morpholin-4-yl-ethylamino)-thiazo-4-one(whichwas obtained in Intermediate 19) according to the procedure ofIntermediate 18 as a yellowish solid (one major isomer); ¹H NMR (300MHz, DMSO-d₆) δ 2.30-2.55(m, 10 H), 3.50-3.70 (m, 6 H), 3.74 (t, J=5.9Hz, 4 H), 7.11 (d, J=8.7 Hz, 2 H), 7.45 (d, J=8.7 Hz, 2 H), 7.50 (s, 1H), 9.46 (brs, 1 H); MS (ES) m/z: 414.9 (MH⁺, 100%), 829.1 ((2M+H)⁺,2%); HRMS Calcd. for C₂₁H₂₆N₄O₃S (M⁺): 414.1726. Found: 414.1734.

Intermediate 21

1-{4-[2-(1-Benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(whichwas obtained in Intermediate 16) and 4-amino-1-benzylpiperidineaccording to the procedures of Intermediate 17 and Intermediate 18 as ayellowish solid (one major isomer); ¹H NMR (300 MHz, DMSO-d₆) δ1.50-4.00(m, 9 H), 2.43 (t, J=5.9 Hz, 4 H), 3.33 (s, 2 H),3.74 (t, J=5.9Hz, 4 H), 7.12 (d, J=8.7 Hz, 2 H), 7.20-7.50 (m, 5 H), 7.44 (d, J=8.7Hz, 2 H), 7.52 (s, 1 H); MS (ES) m/z: 475.0 (MH⁺, 100%), 949.3 ((2M+H)⁺,2%); HRMS Calcd. for C₂₇H₃₀N₄O₂S (M⁺): 474.2089. Found: 474.2085.

Intermediate 22

3-[5-(4-Oxo-piperidin-1-yl)-benzylidene-4-oxo-4,5-dihydrothiazol-2-ylamino]-propionicacid ethyl ester

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(whichwas obtained in Intermediate 16) and β-alanine ethyl ester according tothe procedures of Intermediate 17 and Intermediate 18 as a yellowishsolid (one major isomer); MS (ES) m/z: 402.2 (MH⁺, 100%).

Intermediate 23

N,N-Dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)benzylidene]-2-methylsulfanyl-thiazo-4-one(whichwas obtained in Intermediate 16) and 1,1-dimethylguanidine sulfateaccording to the procedures of Intermediate 17 and Intermediate 18 as ayellowish solid (one major isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 2.49 (t,J=6.0 Hz, 4 H), 2.90-3.20 (m, 6 H), 3.73 (t, J=6.0 Hz, 4 H), 7.10 (d,J=9.0 Hz, 2 H), 7.47 (d, J=9.0 Hz, 2 H), 7.50 (s, 1 H); MS (ES) m/z:372.0 (MH⁺); HRMS Calcd. for C₁₈H₂₂N₅O₂S (MH⁺): 372.1416. Found:372.1404.

Intermediate 24

5-[4-(1,4-Dioxa-8-aza-spiro[4,5]dec-8-yl)benzylidene]-2-hydroxyamino-thiazol-4-one:

A solution of hydroxyamine hydrochloride (2.09 g, 30 mmol) in methanol(50 mL) was treated in portions with potassium tert-butoxide (3.25 g, 29mmol). The mixture was stirred for 30 minutes and then rapidly filteredinto a suspension of5-[4(1,4-dioxa-8-aza-spiro[4,5]dec-6-yl)-benzylidene]-2-thioxothiazolidin-4-one(which was obtained in Intermediate 15)(1.81 g, 5 mmol) in methanol (200mL). The reaction mixture was refluxed overnight. Upon cooling theprecipitated solid was collected to give the title compound as ayellowish solid (one major isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 1.68 (t,J=5.5 Hz, 4 H), 3.16 (d, J=5.2 Hz, 1 H), 3.44 (t, J=5.5 Hz, 4 H), 3.92(s, 4 H), 7.07 (d, J=8.7 Hz, 2 H), 7.40 (d, J=8.7 Hz, 2 H), 7.45 (s, 1H); MS (ES) m/z: 361.8 (MH⁺); HRMS Calcd. for C₁₇H₁₉N₃O₄S (M⁺):361.1096. Found: 361.1113.

Intermediate 25

1-[4-(4-Oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(whichwas obtained in Intermediate 16) and piperidine according to theprocedures of Intermediate 17 and Intermediate 18 as a yellowish solid(one major isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 1.50-1.75(m, 6 H), 2.43(t, J=5.9 Hz, 4 H), 3.55-3.70 (m, 2 H), 3.74 (t, J=5.9 Hz, 4 H),3.80-3.95 (m, 2 H), 7.10 (d, J=8.9 Hz, 2 H), 7.51 (d, J=8.9 Hz, 2 H),7.54 (s, 1 H); MS (ES) m/z: 370.0 (MH⁺, 100%), 739.1 ((2M+H)⁺, 5%); HRMSCalcd. for C₂₀H₂₃N₃O₂S (M⁺): 369.1511. Found: 369.1518.

Intermediate 26

5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-morpholin-4-yl-thiazol-4-one:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)benzylidene]-2-methylsulfanyl-thiazo-4-one(whichwas obtained in Intermediate 16) and morpholine according to theprocedure of Intermediate 17 as a yellowish solid (one major isomer); ¹HNMR (300 MHz, DMSO-d₆) δ 1.68 (brt, J=5.6 Hz, 4 H), 3.45 (brt, J=5.6 Hz,4 H), 3.60-3.70(m, 2H), 3.70-3.80(m, 4 H), 3.90-3.92(m, 2 H), 3.92(s, 4H), 7.05 (d, J=7.6 Hz, 2 H), 7.49 (d, J=7.6 Hz, 2 H), 7.52 (s, 1 H); MS(ES) m/z: 416.0 (MH⁺, 100%); HRMS Calcd. for C₂₁H₂₅N₃O₄S (M⁺): 415.1565.Found: 415.1570.

Intermediate 27

5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-(4-methyl-piperazin-1-yl-thiazol-4-one:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)benzylidene]-2-methylsulfanyl-thiazo-4-one(whichwas obtained in Intermediate 16) and 4-methylpiperazine according to theprocedure of Intermediate 17 as a yellowish solid (one major isomer); ¹HNMR (300 MHz, DMSO-d₆) δ 1.68 (brt, J=5.6 Hz, 4 H), 2.22(s, 3 H),2.40-2.50(m, 4 H), 3.41 (brt, J=5.6 Hz, 4 H), 3.60-3.65(m, 2H),3.90-4.05(m, 2 H), 4.05(s, 4 H), 7.05 (d, J=8.7 Hz, 2 H), 7.46 (d, J=8.7Hz, 2 H), 7.53 (s, 1 H); MS (ES) m/z: 429.0 (MH⁺, 100%); HRMS Calcd. forC₂₂H₂₈N₄O₃S (M⁺): 428.1882. Found: 428.1869.

Intermediate 28

1-[4-(2-Morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-morpholin-4-yl-thiazol-4-one(whichwas obtained in Intermediate 26) according to the procedure ofIntermediate 18 as a yellowish solid (one major isomer); ¹H NMR (300MHz, DMSO-d₆) δ 2.44 (t, J=6.0 Hz, 4 H), 3.60-3.80(m, 10 H),3.85-3.95(m, 2 H), 7.10 (d, J=8.9 Hz, 2 H), 7.51 (d, J=8.9 Hz, 2 H),7.57 (s, 1 H); MS (ES) m/z: 372.0 (MH⁺, 100%); HRMS Calcd. forC₁₉H₂₁N₃O₃S (M⁺): 371.1303. Found: 371.1310.

Intermediate 29

1-{4-[2-(4-Methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one(whichwas obtained in Intermediate 27) according to the procedure ofIntermediate 18 as a yellowish solid (one major isomer); ¹H NMR (300MHz, DMSO-d₆) δ 2.24(s, 3 H), 2.40-2.60(m, 8 H), 3.60-3.70(m, 2 H),3.74(t, J=6.0 Hz, 4 H), 3.85-3.95(m, 2 H), 7.10 (d, J=8.9 Hz, 2 H), 7.51(d, J=8.9 Hz, 2 H), 7.55 (s, 1 H); MS (ES) m/z: 385.0 (MH⁺, 100%); HRMSCalcd. for C₂₀H₂₄N₄O₂S (M⁺): 384.1620. Found: 384.1616.

Intermediate 30

5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-2-hexylamino-thiazol-4-one:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)benzylidene]-2-methylsulfanyl-thiazo-4-one(whichwas obtained in Intermediate 16) and hexylamine according to theprocedure of Intermediate 17 as a yellowish solid (one major isomer); ¹HNMR (300 MHz, DMSO-d₆) δ 0.87 (t, J=6.6 Hz, 3 H), 1.20-1.40(m, 6 H),1.50-1.60(m, 2 H), 1.66 (brt, J=5.6 Hz, 4 H), 3.40-3.60(m, 6 H), 3.92(s,4 H), 7.06 (d, J=8.9 Hz, 2 H), 7.39 (d, J=8.9 Hz, 2 H), 7.48 (s, 1 H),9.50(brs, 1 H); MS (ES) m/z: 430.0 (MH⁺, 100%); HRMS Calcd. forC₂₃H₃₁N₃O₃S (M⁺): 429.2086. Found: 429.2081.

Intermediate 31

2-(3-Dimethylamino-propylamino)-5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-thiazol-4-one:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(whichwas obtained in Intermediate 16) and 3-dimethylaminopropylamineaccording to the procedure of Intermediate 17 as a yellowish solid (onemajor isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 1.60-1.70(m, 6 H), 2.10(s, 6H), 2.25 (t, J=7.0 Hz, 2 H), 3.30-3.50(m, 6 H), 3.85(s, 4 H), 7.07 (d,J=9.0 Hz, 2 H), 7.40 (d, J=9.0 Hz, 2 H), 7.48 (s, 1 H), 9.50(brs, 1 H);MS (ES) m/z: 431.1 (MH⁺, 100%); HRMS Calcd. for C₂₂H₃₀N₄O₃S (M⁺):430.2038. Found: 430.2040.

Intermediate 32

1-[4-(2-Hexylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)benzylidene]-2-hexylamino-thiazol-4-one(whichwas obtained in Intermediate 30) according to the procedure ofIntermediate 18 as a yellowish solid (one major isomer); ¹H NMR (300MHz, DMSO-d₆) δ 0.87(t, J=6.5 Hz, 3 H), 1.20-1.40(m, 6 H), 1.50-1.75(m,2 H), 2.43(t, J=5.9 Hz, 4 H), 3.40-3.55(m, 2 H), 3.74 (t, J=5.9 Hz, 4H), 7.12 (d, J=8.9 Hz, 2 H), 7.44 (d, J=8.9 Hz, 2 H), 7.50 (s, 1 H),9.47(t, J=5.3 Hz, 1 H); MS (ES) m/z: 386.0 (MH⁺, 100%); HRMS Calcd. forC₂₁H₂₇N₃O₂S (M⁺): 385.1824. Found: 385.1809.

Intermediate 33

1-{4-[2-(3-Dimethylamino-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one:

The title compound was prepared from2-(3-dimethylamino-propylamino)-5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-thiazol-4-one(whichwas obtained in Intermediate 31) according to the procedure ofIntermediate 18 as a yellowish solid (one major isomer); ¹H NMR (300MHz, DMSO-d₆) δ 1.60-1.80(m, 2 H), 2.24(s, 6 H), 2.30-2.45(m, 6 H), 3.51(t, J=6.9 Hz, 2 H), 3.74 (t, J=5.9 Hz, 4 H), 7.12 (d, J=9.0 Hz, 2 H),7.44 (d, J=9.0 Hz, 2 H), 7.53 (s, 1 H); MS (ES) m/z: 387.0 (MH⁺, 100%);HRMS Calcd. for C₂₀H₂₆N₄O₂S (M⁺): 386.1776. Found: 386.1768.

Intermediate 34

(2S)-2-{5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pentanedioicacid diethyl ester:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(which was obtained in Intermediate 16) and diethyl L-glutamatehydrochloride according to the procedure of Intermediate 24 as ayellowish solid (one major isomer); ¹H NMR (300 MHz, DMSO-d₆) δ 1.17(t,J=7.1 Hz, 3 H), 1.21 (t, J=7.1 Hz, 3 H), 1.68(brt, J=5.6 Hz, 4 H),3.45(brt, J=5.6 Hz, 4 H), 3.91(s, 4H), 4.05(q, J=7.1 Hz, 2 H), 4.15(q,J=7.1 Hz, 2 H), 4.60-4.70(m, 1 H), 7.07 (d, J=9.0 Hz, 2 H), 7.42 (d,J=9.0 Hz, 2 H), 7.52 (s, 1 H); MS (ES) m/z:532.0 (MH⁺, 100%); HRMSCalcd. for C₂₆H₃₃N₃O₇S (MH⁺): 532.2117. Found: 532.2115.

Intermediate 35

5-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl-cyanamide:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-benzylidene]-2-methylsulfanyl-thiazo-4-one(whichwas obtained in Intermediate 16) and cyanamide according to theprocedure of Intermediate 24 as a red solid (one major isomer); ¹H NMR(300 MHz, DMSO-d₆) δ 1.68(brt, J=5.6 Hz, 4 H), 3.45(brt, J=5.6 Hz, 4 H),3.92(s, 4H), 7.05 (d, J=9.0 Hz, 2 H), 7.33(s, 1 H), 7.39 (d, J=9.0 Hz, 2H); MS (ES) m/z:370.9 (MH⁺, 100%); HRMS Calcd. for C₁₈H₁₉N₄O₃S (MH⁺):371.1172. Found: 371.1172.

Intermediate 36

4-Oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl-cyanamide:

The title compound was prepared from5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-yl-cyanamide(whichwas obtained in Intermediate 35) according to the procedure ofIntermediate 18 as a red solid (one major isomer); ¹H NMR (300 MHz,DMSO-d₆) δ 2.43(t, J=6.0 Hz, 4 H), 3.76(t, J=6.0 Hz, 4 H), 7.12 (d,J=9.0 Hz, 2 H), 7.36(s, 1 H), 7.47 (d, J=9.0 Hz, 2 H); MS (ES) m/z:326.7(MH⁺, 100%); HRMS Calcd. for C₁₆H₁₅N₄O₂S (MH⁺): 327.0910. Found:327.0909.

Intermediate 37

5-[4-(2,2-Diethoxy-ethoxy)-benzylidene]-2-thioxo-thiazolidin-4-one:

Under nitrogen, a mixture of 4-hydroxybenzaldehyde (1.71 g, 14 mmol),bromoacetaldehyde diethyl acetate (37.4 g, 190 mmol), tetrabutylammoniumbromide (0.61 g, 1.9 mmol) and potassium carbonate (26.1 g, 190 mmol) in100 mL of toluene was refluxed for 2.5 days. After cooling the mixturewas dissolved in water and extracted with dichloromethane. The organiclayers were dried over magnesium sulfate and concentrated. The residuewas purified by column chromatography (eluent: hexanes/ethyl acetate) togive 4-(2,2-diethoxyethoxy) benzaldehyde as a colorless oil (2.60 g,79%). The title compound was prepared from 4-(2,2-diethoxyethoxy)benzaldehyde and rhodanine according to the procedure of Intermediate 15as a yellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ 1.14(t, J=7.1 Hz, 6H), 3.50-3.80 (m, 4 H), 4.04(d, J=5.0 Hz, 2 H), 4.05-4.30(m, 2 H), 6.06(t, J=5.0 Hz, 1 H), 7.14 (d, J=9.0 Hz, 2 H), 7.60 (d, J=9.0 Hz, 2 H),7.63(s, 1 H); MS (ES) m/z:351.7 ((M-H)⁻, 100%); HRMS Calcd. forC₁₆H₂₀NO₄S₂ (MH⁺): 353.0775. Found: 353.0757.

Intermediate 38

5-[4-(2,2-Diethoxy-ethoxy)-benzylidene]-2-piperidin-1-yl-thiazol-4-one:

A mixture of5-[4-(2,2-diethoxy-ethoxy)-benzylidene]-2-thioxo-thiazolidin-4-one(which was obtained in Intermediate 37)(1.19 g, 5 mmol), rhodanine (0.67g, 5 mmol) and piperidine (1.72 g, 20.2 mmol) in ethanol (50 mL) wasrefluxed for 2 hours. After cooling to room temperature hexanes (70 mL)were added and the solid which was formed was collected to give thetitle compound as a yellowish solid (1.4 g, 69%); ¹H NMR (300 MHz,DMSO-d₆) δ 1.14(t, J=7.1 Hz, 6 H), 1.55-1.75(m, 6 H), 3.40-3.80 (m, 6H), 3.85-3.95(m, 2 H), 4.02(d, J=5.2 Hz, 2 H), 4.82 (t, J=5.2 Hz, 1 H),7.11 (d, J=7.6 Hz, 2 H), 7.57 (d, J=7.6 Hz, 2 H), 7.58(s, 1 H); MS (ES)m/z: 404.9 (MH⁺, 100%); HRMS Calcd. for C₂₁H₂₈N₂O₄S (M⁺): 404.1770.Found: 404.1780.

Intermediate 39

4-(4-Oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenoxy]-acetaldehydehydrate:

The title compound was prepared from5-[4-(2,2-diethoxy-ethoxy)-benzylidene]-2-piperidin-1-yl-thiazol-4-one(whichwas obtained in Intermediate 38) according to the procedure ofIntermediate 18 as a yellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ1.50-1.75(m, 6 H), 3.55-3.70 (m, 2 H), 3.80-3.95(m, 4 H), 5.05-5.65(m, 1H), 6.12(d, J=6.6 Hz, 2 H), 7.07 (d, J=9.0 Hz, 2 H), 7.57 (d, J=9.0 Hz,2 H), 7.58(s, 1 H); MS (ES) m/z: 348.9 ((M+H₂O+H) ⁺, 100%); HRMS Calcd.for C₁₇H₁₈N₂O₃S (M⁺): 330.1038. Found: 330.1040.

Intermediate 40

5-[4-(4-Oxo-pyridin-1-yl)-benzylidene]-2-hydroxyamino-thiazo-4-one

The title compound was prepared from5-[4-(1,4-ioxa-8-aza-spiro[4,5]dec-8-yl)benzylidene]-2-hydroxyamino-thiazol-4-one(whichwas obtained in Intermediate 24) according to the procedure ofIntermediate 18 as a yellowish solid (one major isomer); MS (ES) m/z:318.2 (MH⁺, 100%).

The following procedures describe the preparation of representativeexamples of this invention.

EXAMPLE 1

4-((2S)-2-Hydroxy-3-{1-[4-(2-methylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydrobenzoimidazol-2-one:

1-[4-(2-Methylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 18)(0.15 g, 0.47 mmol) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one(Jesudason, C. D., et al., EP 0 764 640) (0.11 g, 0.47 mmol) were mixedin dimethylformamide (15 mL) and then treated with sodiumtriacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.15 mL).After stirring at room temperature under a nitrogen atmosphere for oneday the mixture was poured into a saturated aqueous sodium bicarbonatesolution. The precipitate was collected and purified by columnchromatography (eluent: methanol/methylene chloride) to give the titlecompound as a pale yellowish solid(0.16 g, 65%); mp>160° C. (dec.); ¹HNMR (300 MHz, DMSO-d₆) δ 1.20-1.45 (m, 2 H), 1.75-2.00 (m, 2 H),2.60-3.00 (m, 5 H), 3.05 (s, 3 H), 3.75-4.15 (m, 5 H), 6.57 (d, J=7.8Hz, 1 H), 6.62 (d, J=8.1 Hz, 1 H), 6.87 (t, J=8.1 Hz, 1 H), 7.02 (d,J=8.7 Hz, 2 H), 7.38 (d, J=8.7 Hz, 2 H), 7.47 (s, 1 H), 10.56 (s, 1 H),10.70 (brs, 1 H); MS (ES) m/z: 262.1 ((M+2H)²⁺, 100%); 522.9 (MH⁺, 75%);HRMS Calcd. for C₂₆H₃₁N₆O₄S (MH⁺): 523.2128. Found: 523.2142.

EXAMPLE 2

4-[(2S)-2-Hydroxy-3-(1-{4-[2-(2-morpholin-4-ylethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-propoxy]-1,3-dihydrobenzoimidazol-2-one:

The title compound was prepared from1-{4-[2-(2-morpholin-4-ylethylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(whichwas obtained in Intermediate 20) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one(Jesudason, C. D., et al., EP 0 764 640) according to the procedure ofExample 1 as a pale yellowish solid; mp>140° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.45 (m, 2 H), 1.75-2.00 (m, 2 H), 2.43 (t, J=4.7 Hz, 2H), 2.50-3.70 (m, 13 H), 3.59 (t, J=4.7 Hz, 2 H), 3.75-4.15 (m, 5 H),4.86 (brs, 1 H), 6.57 (d, J=7.5 Hz, 1 H), 6.62 (d, J=7.5 Hz, 1 H), 6.87(t, J=8.1 Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.38 (d, J=9.0 Hz, 2 H),7.47 (s, 1 H), 9.47 (s, 1 H), 10.57 s, 1 H), 10.70 (brs, 1 H); MS (ES)m/z: 311.5 ((M+2H)²⁺, 100%); 621.9 (MH⁺, 15%); HRMS Calcd. forC₃₁H₄₀N₇O₅S (MH⁺): 622.2812. Found: 622.2811.

EXAMPLE 3

4-[(2S)-3-(1-{4-[2-(1-Benzyl-piperidin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-2-hydroxy-propoxy]-1,3-dihydro-benzoimidazol-2-one:

The title compound was prepared from1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(whichwas obtained in Intermediate 21) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one(Jesudason, C. D., et al., EP 0 764 640) according to the procedure ofExample 1 as a pale yellowish solid; mp>165° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H),2.06 (brt, J=9.9 Hz, 2 H), 2.55-2.95 (m, 6 H), 3.47 (s, 2 H), 3.75-4.05(m, 5 H), 4.87 (brs, 1 H), 6.57 (d, J=7.5 Hz, 1 H), 6.61 (d, J=8.1 Hz, 1H), 6.84 (t, J=8.1 Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.50 (m, 8H), 9.46 (brs, 1 H), 10.57 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z:341.6 ((M+2H)²⁺, 100%); 682.1 (MH⁺, 5%); HRMS Calcd. for C₃₇H₄₄N₇O₄S(MH⁺): 682.3176. Found: 682.3211.

EXAMPLE 4

2-(1-Benzyl-piperidin-4-ylamino)-5-(4-{(2S)-4-[2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-thiazol-4-one:

The title compound was prepared from1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(which was obtained in Intermediate 21) and4-[(2S)-3-amino-2-hydroxy-propoxyl]-phenol (which was obtained inIntermediate 5) according to the procedure of Example 1 as a paleyellowish solid; mp>175° C. (dec.); ¹H NMR (300 MHz, DMSO-d₆) δ1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H), 2.06 (brt,J=9.5 Hz, 2 H), 2.55-2.95 (m, 6 H), 3.47 (s, 2 H), 3.70-4.00 (m, 5 H),4.92 (brs, 1 H), 6.66 (d, J=6.8 Hz, 2 H), 6.75 (d, J=6.8 Hz, 2 H), 7.02(d, J=9.0 Hz, 2 H), 7.20-7.50 (m, 8 H), 8.89 (brs, 1 H), 9.29 (brs, 1H); MS (ES) m/z:321.6 ((M+2H)²⁺, 100%); 642.1 (MH⁺, 5%); HRMS Calcd. forC₃₆H₄₄N₅O₄S (MH⁺): 642.3114. Found: 642.3095.

EXAMPLE 5

N-{5-[2-(1-{4-[2-(1-Benzyl-piperidin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}-methanesulfonamide:

The title compound was prepared from1-{4-[2-(1-benzyl-piperdin-4-ylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(which was obtained in Intermediate 21) andN-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Intermediate 9) according to the procedure ofExample 1 as a pale yellowish solid; mp>210° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.40 (m, 2 H), 1.40-1.65 (m, 2 H), 1.70-2.00 (m, 4 H),2.06 (brt, J=9.8 Hz, 2 H), 2.50-3.50 (m, 6 H), 2.92 (s, 3 H), 3.47 (s, 2H), 3.70-4.00 (m, 2 H), 4.47 (dd, J=7.9, 4.3 Hz, 1 H), 6.81 (d, J=8.2Hz, 1 H), 6.95-7.05 (m, 2 H), 7.17 (d, J=1.9 Hz, 1 H), 7.20-7.55 (m, 8H); MS (ES) m/z:353.1 ((M+2H)²⁺, 100%); 705.1 (MH⁺, 5%); HRMS Calcd. forC₃₆H₄₅N₆O₅S₂ (MH⁺): 705.2893. Found: 705.2921.

EXAMPLE 6

N′-[5-(4-{4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-yl]-N,N-dimethyl-guanidine:

The title compound was prepared fromN,N-dimethyl-4-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(which was obtained in Intermediate 23) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one(Jesudason, C. D., et al., EP 0 764 640) according to the procedure ofExample 1 as a pale yellowish solid; mp>165° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.40 (m, 2 H), 1.70-2.00 (m, 4 H), 2.50-3.00 (m, 5 H),3.33 (s, 6 H), 3.70-4.10 (m, 5 H), 4.86 (brs, 1 H), 6.56 (d, J=7.5 Hz, 1H), 6.61 (d, J=8.1 Hz, 1 H), 6.88 (t, J=8.1 Hz, 1 H), 7.02 (d, J=9.0 Hz,2 H), 7.40 (d, J=9.0 Hz, 2 H), 7.47 (s, 1 H), 10.57 (s, 1 H), 10.70(brs, 1 H); MS (ES) m/z: 290.0 ((M+2H)²⁺, 100%); 579.1 (MH⁺, 5%); HRMSCalcd. for C₂₈H₃₅N₈O₄S (MH⁺): 579.2502. Found: 579.2534.

EXAMPLE 7

N-{5-[2-(1-{4-[2-(N′,N′-Dimethyl-guanidino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}-methanesulfonamide:

The title compound was prepared fromN,N-dimethyl-4-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(which was obtained in Intermediate 23) andN-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Intermediate 9) according to the procedure ofExample 1 as a pale yellowish solid; mp>145° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.40 (m, 2 H), 1.70-2.00 (m, 2 H), 2.00-3.50 (m, 5 H),2.91 (s, 6 H), 3.70-3.90 (m, 2 H), 4.48 (dd, J=7.9, 4.3 Hz, 1 H), 6.81(d, J=8.3Hz, 1 H), 6.95-7.10 (m, 3 H), 7.18 (d, J=2.0 Hz, 1 H), 7.41 (d,J=8.9 Hz, 2 H), 7.47 (s, 1 H); C₂₇H₃₆N₇O₅S₂ (MH⁺): 602.2219. Found:602.2225.

EXAMPLE 8

3-[5-(4-{4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-propionicacid ethyl ester:

The title compound was prepared from3-[5-(4-oxo-piperidin-1-yl)-benzylidene-4-oxo-4,5-dihydrothiazol-2-ylamino]-propionicacid ethyl ester (which was obtained in Intermediate 22) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one(Jesudason, C. D., et al., EP 0 764 640) according to the procedure ofExample 1 as a pale yellowish solid; mp>120° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.19 (t, J=7.1 Hz, 3 H), 1.20-1.40 (m, 2 H), 1.85-2.00 (m, 2H), 2.50-3.00 (m, 7H), 3.50-4.10 (m, 7 H), 4.10 (q, J=7.1 Hz, 2 H), 6.57(d, J=7.8 Hz, 1 H), 6.61 (d, J=8.4 Hz, 1 H), 6.82 (t, J=8.1 Hz, 1 H),7.04 (d, J=7.8 Hz, 2 H), 7.40 (d, J=7.8 Hz, 2 H), 7.47 (s, 1 H), 10.58(s, 1 H), 10.71 (brs, 1 H); MS (ES) m/z: 305.0 ((M+2H)²⁺, 100%); 609.1(MH³⁰ , 20%); HRMS Calcd. for C₃₀H₃₇N₆O₆S (MH⁺): 609.2495. Found:609.2486.

EXAMPLE 9

3-[5-(4-{4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-propionicacid:

The title compound was prepared from3-[5-(4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-propionicacid ethyl ester(which was obtained in Example 8)by NaOH hydrolysis as apale yellowish solid; MS (ES) m/z: 291.0 ((M+2H)₂₊, 100%); 581.0 (MH⁺,30%); HRMS Calcd. for C₂₈H₃₃N₆O₆S (MH⁺): 581.2182. Found: 581.2195.

EXAMPLE 10

4-((2S)-2-Hydroxy-3-{1-[4-(2-hydroxyamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one:

The title compound was prepared from5-[4-(4-oxo-pyridin-1-yl)-benzylidene]-2-hydroxyamino-thiazo-4-one(which was obtained in Intermediate 40) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one(Jesudason, C. D., et al., EP 0 764 640) according to the procedure ofExample 1 as a pale yellowish solid; mp 201-213° C. (dec.); ¹H NMR (300MHz, DMSO-d₆) δ 1.30-1.45 (m, 2 H), 1.85-2.00 (m, 2 H), 2.60-3.00 (m, 5H), 3.60-4.10 (m, 5 H), 6.57 (d, J=7.7 Hz, 1 H), 6.62 (d, J=8.2 Hz, 1H), 6.88 (t, J=8.1 Hz, 1 H), 7.04 (d, J=9.0 Hz, 2 H), 7.36 (s, 1 H),7.42 (d, J=9.0 Hz, 2 H), 10.50-10.70 (m, 2 H); MS (ES) m/z: 525.0 (MH⁺);HRMS Calcd. for C₂₅H₂₉N₆O₅S (MH⁺): 525.1920. Found: 525.1914.

EXAMPLE 11

N-[2-Hydroxy-5-(1-hydroxy-2-{1-[4-(2-hydroxyamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide:

The title compound was prepared from5-[4-(4-oxo-pyridin-1-yl)-benzylidene]-2-hydroxyamino-thiazo-4-one(which was obtained in Intermediate 40) andN-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Intermediate 9) according to the procedure ofExample 1 as a pale yellowish solid; mp>190° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.25-1.45 (m, 2 H), 1.70-2.00 (m, 2 H), 2.50-3.00 (m, 5 H),2.98 (s, 3 H), 3.80-3.90 (m, 2 H), 4.50 (dd, J=8.2 4.1 Hz, 1 H), 6.83(d, J=8.1 Hz, 1 H), 6.95-7.10 (m, 3 H), 7.18 (d, J=1.8 Hz, 1 H), 7.36(s, 1 H), 7.39 (d, J=6.6 Hz, 2 H); MS (ES) m/z: 547.9 (MH⁺); HRMS Calcd.for C₂₄H₃₀N₅O₆S₂ (MH⁺): 548.1638. Found: 548.1663.

EXAMPLE 12

4-((2S)-2-Hydroxy-3-{1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one:

The title compound was prepared from1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 25) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one(Jesudason, C. D., et al., EP 0 764 640) according to the procedure ofExample 1 as a pale yellowish solid; mp>140° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.40 (m, 2 H), 1.55-1.75 (m, 6 H), 1.80-2.00 (m, 2 H),2.60-2.95 (m, 5 H), 3.50-4.10 (m, 9 H), 4.89 (brs, 1 H), 6.57 (d, J=7.8Hz, 1 H), 6.62 (d, J=8.2 Hz, 1 H), 6.87 (t, J=8.1 Hz, 1 H), 7.01 (d,J=8.9 Hz, 2 H), 7.45 (d, J=8.9 Hz, 2 H), 7.51 (s, 1 H), 10.60 (s, 1 H),10.70 (brs, 1 H); MS (ES) m/z: 289.1 ((M+2H)²⁺, 100%), 577.1 (MH⁺, 50%);HRMS Calcd. for C₃₀H₃₇N₆O₄S (MH⁺): 577.2597. Found: 577.2625.

EXAMPLE 13

N-[2-Hydroxy-5-((1R)-1-hydroxy-2-{1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide:

The title compound was prepared from1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 25) andN-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Intermediate 10) according to the procedure ofExample 1 as a pale yellowish solid; mp>120° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.40 (m, 2 H), 1.55-1.75 (m, 6 H), 1.80-2.00 (m, 2 H),2.60-3.00 (m, 5 H), 2.92 (s, 3 H), 3.50-3.90 (m, 6 H), 4.49 (dd, J=8.0,4.2 Hz, 1 H), 6.82 (d, J=8.5 Hz, 1 H), 6.95-7.07 (m, 3 H), 7.18 (d,J=2.0 Hz, 1 H), 7.45 (d, J=8.9 Hz, 2 H),7.50 (s, 1 H); MS (ES) m/z:300.6 ((M+2H)²⁺, 100%), 600.1 (MH⁺, 50%); HRMS Calcd. for C₂₉H₃₇N₅O₅S₂(MH⁺): 600.2314. Found: 600.2330.

EXAMPLE 14

N-[2-Hydroxy-5-((2S)-2-hydroxy-3-{1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-phenyl]-methanesulfonamide:

The title compound was prepared from1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 25) andN-[5-((2S)-3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Intermediate 14) according to the procedure ofExample 1 as a yellowish solid; mp>95° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.40 (m, 2 H), 1.55-1.70 (m, 6 H), 1.85-2.00 (m, 2 H),2.55-2.90 (m, 6 H), 2.92 (s, 3 H), 3.60 (br s, 2 H), 3.70-3.95 (m, 6 H),6.61 (dd, J=8.8, 2.9 Hz, 1 H), 6.75-6.80 (m, 2 H), 7.02 (d, J=9.0 Hz, 2H), 7.45 (d, J=9.0 Hz, 2 H), 7.50 (s, 1 H); MS (ES) m/z: 315.6((M+2H)²⁺, 100%); 630.1 (MH⁺, 100%); HRMS Calcd. for C₃₀H₄₀N₅O₆S₂ (MH⁺):630.2420. Found: 630.2397.

EXAMPLE 15

8-Hydroxy-5-((2S)-2-hydroxy-3-{1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-3,4-dihydro-1H-quinolin-2-one:

The title compound was prepared from1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 25) and5-((2S)-3-amino-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one(which was obtained in Intermediate 12) according to the procedure ofExample 1 as a yellowish solid; mp>120° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.40 (m, 2 H), 1.55-1.70 (m, 6 H), 1.85-2.00 (m, 2 H),2.43 (t, J=7.9 Hz, 2.55-2.90 (m, 9 H), 3.60 (br s, 2 H), 3.70-3.95 (m, 6H), 6.44 (d, J=9.0 Hz, 1 H), 6.69 (d, J=9.0 Hz, 1 H), 7.02 (d, J=9.0 Hz,2 H), 7.44 (d, J=9.0 Hz, 2 H), 7.50 (s, 1 H), 8.82 (s, 1 H); MS (ES)m/z: 303.6 ((M+2H)²⁺, 100%); 606.1 (MH⁺, 10%); HRMS Calcd. forC₃₂H₄₀N₅O₅S (MH⁺): 606.2750. Found: 606.2711.

EXAMPLE 16

5-(4-{4-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-piperidin-1-yl-thiazol-4-one:

The title compound was prepared from1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 25) and4-((2S)-3-amino-2-hydroxy-propoxy)-phenol (which was obtained inIntermediate 5) according to the procedure of Example 1 as a yellowishsolid; mp>85° C. (dec.); ¹H NMR (300 MHz, DMSO-d₆) δ 1.20-1.40 (m, 2 H),1.55-1.70 (m, 6 H), 1.85-2.00 (m, 2 H), 2.55-2.95 (m, 6 H), 3.60 (br s,2 H), 3.70-3.95 (m, 6 H), 6.66 (d, J=9.0 Hz, 2 H), 6.75 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0 Hz, 1 H), 7.48 (d, J=9.0 Hz, 1 H), 7.50 (s, 1 H),8.90 (brs, 1 H); MS (ES) m/z: 269.0 ((M+2H)²⁺, 100%); 537.6 (MH⁺, 10%);HRMS Calcd. for C₂₉H₃₇N₄O₄S (MH⁺): 537.2536. Found: 537.2500.

EXAMPLE 17

N′-[5-(4-{4-[(2S)-2-Hydroxy-3-(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-5-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-yl]-N,N-dimethyl-guanidine:

The title compound was prepared fromN,N-dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(whichwas obtained in Intermediate 23) and5-((2S)-3-amino-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one(which was obtained in Intermediate 12) according to the procedure ofExample 1 as a yellowish solid; mp>140° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.40 (m, 2 H), 1.80-1.95 (m, 6 H), 2.40 (t, J=7.9 Hz, 2H), 2.55-3.20 (m, 12 H), 3.70-3.95 (m, 6 H), 6.44 (d, J=8.7 Hz, 1 H),6.60 (d, J=8.7 Hz, 1 H), 7.00 (d, J=8.9 Hz, 2 H), 7.41 (d, J=8.9 Hz, 2H), 7.47 (s, 1 H), 8.82 (brs, 1 H); MS (ES) m/z: 304.6 ((M+2H)²⁺, 100%);608.1 (MH⁺, 10%); HRMS Calcd. for C₃₀H₃₈N₇O₅S (MH⁺): 608.2655. Found:608.2655.

EXAMPLE 18

4-((2S)-2-Hydroxy-3-{1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one:

The title compound was prepared from1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(whichwas obtained in Intermediate 28) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one(Jesudason, C. D., et al., EP 0 764 640) according to the procedure ofExample 1 as a yellowish solid; mp>150° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.55-2.95 (m, 4 H),3.60-4.10 (m, 14 H), 4.90 (br s, 1 H), 6.56 (d, J=7.8 Hz, 1 H), 6.62 (d,J=8.0 Hz, 1 H), 6.87 (dd, J=7.9, 7.9 Hz, 1 H), 7.02 (d, J=8.9 Hz, 2 H),7.45 (d, J=8.9 Hz, 2 H), 7.54 (s, 1 H), 10.65(s, 1 H), 10.75 (brs, 1 H);MS (ES) m/z: 290.0 ((M+2H)²⁺, 100%); 579.1 (MH⁺, 80%); HRMS Calcd. forC₂₉H₃₆N₆O₅S (MH⁺): 579.2390. Found: 579.2392.

EXAMPLE 19

4-[(2S)-2-Hydroxy-3-(1-{4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-ylamino)-propoxy]-1,3-dihydro-benzoimidazol-2-one:

The title compound was prepared from1-{4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(whichwas obtained in Intermediate 29) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one(Jesudason, C. D., et al., EP 0 764 640) according to the procedure ofExample 1 as a yellowish solid; mp>150° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.40 (m, 2 H), 1.85-2.00 (m, 2 H), 2.24 (s, 3 H),2.40-3.00 (m, 11H), 3.50-4.10 (m, 7 H), 6.56 (d, J=8.1Hz, 1 H), 6.62 (d,J=8.1Hz, 1 H), 6.84 (dd, J=8.1, 8.1Hz, 1 H), 7.02 (d, J=9.0 Hz, 2 H),7.48 (d, J=9.0 Hz, 2 H), 7.52 (s, 1 H), 10.3-11.0 (brs, 2 H); MS (ES)m/z: 296.5 ((M+2H)²⁺, 100%); 592.1 (MH⁺, 20%); HRMS Calcd. forC₃₀H₃₈N₇O₄S (MH⁺): 592.2760. Found: 592.2685.

EXAMPLE 20

N′-(5-{4-[4-((2S)-2-Hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-4-oxo-4,5-dihydro-thiazol-2-yl)-N,N-dimethyl-guanidine:

The title compound was prepared fromN,N-dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(whichwas obtained in Intermediate 23) and (2S)-1-amino-3-phenoxy-propan-2-ol(which was obtained in Intermediate 3) according to the procedure ofExample 1 as a yellowish solid; mp>205° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.20-1.40 (m, 2 H), 1.75-1.95 (m, 2 H), 2.50-3.70 (m, 9 H),3.70-4.00 (m, 7 H), 4.95 (brs, 1 H), 6.64-6.94 (m, 3 H), 7.01(d, J=8.9Hz, 2 H), 7.27-7.30(m, 2 H), 7.41 (d, J=8.9 Hz, 2 H), 7.47 (s, 1 H); MS(ES) m/z: 262.0 ((M+2H)²⁺, 100%); 523.0 (MH⁺, 10%); HRMS Calcd. forC₂₇H₃₅N₆O₃S (MH⁺): 523.2491. Found: 523.2511.

EXAMPLE 21

N′-[5-(4-{4-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-yl]-N,N-dimethyl-guanidine:

The title compound was prepared fromN,N-dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(whichwas obtained in Intermediate 23) and4-((2S)-3-amino-2-hydroxy-propoxy)-phenol (which was obtained inIntermediate 5) according to the procedure of Example 1 as a yellowishsolid; ¹H NMR (300 MHz, DMSO-d₆) δ 1.20-1.40 (m, 2 H), 1.75-1.95 (m, 2H), 2.50-3.30 (m, 9 H), 3.70-3.90 (m, 7 H), 4.90 (brs, 1 H), 6.66 (d,J=6.8 Hz, 1 H), 6.74 (d, J=6.8 Hz, 1 H), 7.01 (d, J=8.8 Hz, 2 H), 7.41(d, J=8.8 Hz, 2 H), 7.47 (s, 1 H); MS (ES) m/z: 270.0 ((M+2H)²⁺, 100%);539.1 (MH⁺, 10%); HRMS Calcd. for C₂₇H₃₅N₆O₄S (MH⁺): 539.2441. Found:539.2422.

EXAMPLE 22

5-{4-[4-((2S)-2-Hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-2-morpholin-4-yl-thiazol-4-onedihydrochloride salt:

The free base was prepared from1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 28) and(2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Intermediate3) according to the procedure of Example 1. The free base was dissolvedin methanol/dichloromethane and treated with hydrogen chloride gas.After concentrated the solvents the product was obtained as a yellowishsolid; mp>160° C. (dec.); ¹H NMR (300 MHz, DMSO-d₆) δ 1.60-1.90 (m, 2H), 2.05-2.25 (m, 2 H), 2.80-3.30 (m, 7 H), 3.60-4.40 (m, 11H),6.90-7.10(m, 3 H), 7.14(d, J=8.7 Hz, 2 H), 7.51 (d, J=8.7 Hz, 2 H), 7.57(s, 1 H), 8.92(brs, 1 H), 9.36(brs, 1 H); MS (ES) m/z: 262.1 ((M+2H)²⁺,100%); 523.1(MH⁺, 30%); HRMS Calcd. for C₂₈H₃₅N₄O₃S (MH⁺): 523.2379.Found: 523.2394.

EXAMPLE 23

5-(4-{4-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-morpholin-4-yl-thiazol-4-one:

The title compound was prepared from1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(whichwas obtained in Intermediate 28) and(2S)-1-amino-3-(4-hydroxy-phenoxy)-propan-2-ol (which was obtained inIntermediate 5) according to the procedure of Example 1 as a yellowishsolid; mp>100° C. (dec.); ¹H NMR (300 MHz, DMSO-d₆) δ 1.20-1.40 (m, 2H), 1.80-1.95 (m, 2 H), 2.50-3.00 (m, 7 H), 3.60-4.00 (m, 11H), 6.66(d,J=9.2 Hz, 2 H), 6.74 (d, J=8.9 Hz, 2 H), 7.02(d, J=9.2 Hz, 2 H), 7.45(d,J=8.9 Hz, 2 H), 7.54 (s, 1 H); MS (ES) m/z: 270.0 ((M+2H)²⁺, 100%);539.1(MH⁺, 40%); HRMS Calcd. for C₂₈H₃₅N₄O₅S (MH⁺): 539.2328. Found:539.2322.

EXAMPLE 24

5-(4-{4-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-(4-methyl-piperazin-1-yl)-thiazol-4-one:

The title compound was prepared from1-{4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(which was obtained in Intermediate 29) and(2S)-1-amino-3-(4-hydroxy-phenoxy)-propan-2-ol (which was obtained inIntermediate 5) according to the procedure of Example 1 as a yellowishsolid; mp>210° C. (dec.); ¹H NMR (300 MHz, DMSO-d₆) δ 1.20-1.40 (m, 2H), 1.80-1.95 (m, 2 H), 2.24 (s, 3 H), 2.40-4.00 (m, 18 H), 6.64(d,J=8.9 Hz, 2 H), 6.73 (d, J=8.9 Hz, 2 H), 7.00(d, J=8.9 Hz, 2 H), 7.45(d,J=8.9 Hz, 2 H), 7.52 (s, 1 H), 8.89(brs, 1 H); MS (ES) m/z: 276.6((M+2H)²⁺, 100%); 552.0(MH⁺, 10%); HRMS Calcd. for C₂₉H₃₈N₅O₄S (MH⁺):552.2645. Found: 552.2634.

EXAMPLE 25

5-(4-{4-[(2R)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-piperidin-1-yl}-benzylidene)-2-morpholin-4-yl-thiazol-4-one:

The title compound was prepared from1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(whichwas obtained in Intermediate 28) and(1R)-2-amino-1-(3-chloro-phenyl)-ethanol(which was obtained inIntermediate 1) according to the procedure of Example 1 as a yellowishsolid; mp>70° C. (dec.); ¹H NMR (300 MHz, DMSO-d₆) δ 1.20-1.40 (m, 2 H),1.70-1.95 (m, 2 H), 2.60-2.90 (m, 7 H), 3.50-4.00(m, 8 H), 4.55-4.65(m,1 H), 5.46 (brs, 1H), 7.02 (d, J=9.0 Hz, 2 H), 7.25-7.45 (m, 7 H), 7.54(s, 1 H); MS (ES) m/z: 527.1(MH+, 100%); HRMS Calcd. for C₂₇H₃₂ClN₄O₃S(MH⁺): 527.1884. Found: 527.1863.

EXAMPLE 26

2-(3-Dimethylamino-propylamino)-5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-thiazol-4-one:

The title compound was prepared from1-{4-[2-(3-dimethylamino-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one(whichwas obtained in Intermediate 33) and(2S)-1-amino-3-phenoxy-propan-2-ol(which was obtained in Intermediate 3)according to the procedure of Example 1 as a yellowish solid; mp166-168° C. (dec.); ¹H NMR (300 MHz, DMSO-d₆) δ 1.20-1.40 (m, 10 H),1.60-1.80 (m, 2 H), 1.80-2.00 (m, 2 H), 2.19 (s, 6 H), 2.25 (t, J=6.8Hz, 2 H), 2.55-3.00(m, 5 H), 3.50-4.05(m, 7 H), 6.65-6.95(m, 3 H), 7.02(d, J=9.0 Hz, 2 H), 7.20-7.30 (m, 2 H), 7.40 (d, J=9.0 Hz, 2 H), 7.48(s, 1 H); MS (ES) m/z: 269.6 ((M+2H)²⁺, 100%), 538.1(MH⁺, 10%); HRMSCalcd. for C₂₉H₄₀N₅O₃S (MH⁺): 538.2852. Found: 538.2885.

EXAMPLE 27

2-Hexylamino-5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-thiazol-4-one:

The title compound was prepared from1-[4-(2-hexylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(whichwas obtained in Intermediate 32) and(2S)-1-amino-3-phenoxy-propan-2-ol(which was obtained in Intermediate 3)according to the procedure of Example 1 as a yellowish solid; mp182-184° C. (dec.); 1H NMR (300 MHz, DMSO-d₆) δ 0.87(t, J=6.5 Hz, 3 H),1.20-1.40 (m, 10 H), 1.50-1.65 (m, 2 H), 1.80-1.95 (m, 2 H),2.60-4.00(m, 10 H), 6.85-6.95(m, 3 H), 7.02 (d, J=9.0 Hz, 2 H),7.20-7.35 (m, 2 H), 7.40 (d, J=9.0 Hz, 2 H), 7.45 (s, 1 H), 9.62 (brs, 1H); MS (ES) m/z: 269.1 ((M+2H)²⁺, 100%), 537.1(MH⁺, 20%); HRMS Calcd.for C₃₀H₄₁N₄O₃S (MH⁺): 537.2899. Found: 537.2875.

EXAMPLE 28

N-[5-((2R)-2-{1-[4-(2-Cyanoamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide:

The title compound was prepared from4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl-cyanamide(whichwas obtained in Intermediate 36) andN-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Intermediate 10) according to the procedure of Example 1as a yellowish solid; mp>300° C. (dec.); ¹H NMR (300 MHz, DMSO-d₆) δ1.40-1.60 (m, 10 H), 1.90-2.10 (m, 2 H), 2.70-3.00 (m, 3 H), 2.95(s, 3H), 3.80-4.00 (m, 4 H), 4.67 (brd, J=7.2 Hz, 1 H), 6.81 (d, J=8.5 Hz, 1H), 6.90-7.10 (m, 3 H), 7.23 (d, J=1.9 Hz, 1 H), 7.33 (s, 1 H), 7.40 (d,J=8.5 Hz, 2 H); MS (ES) m/z: 557.0(MH⁺, 100%); HRMS Calcd. forC₂₅H₂₉N₆O₅S₂ (MH⁺): 557.1641. Found: 557.1674.

EXAMPLE 29

(2S)-2-[5-(4-{4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-pentanedioicacid:

The title compound was prepared from(2S)-2-{5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pentanedioicacid diethyl ester (which was obtained in Intermediate 34) and(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one(Jesudason, C. D., et al., EP 0 764 640) according to the procedures ofIntermediate 18, Example 1 and Example 9 as a yellowish solid; mp>270°C. (dec.); ¹H NMR (300 MHz, DMSO-d₆) δ 1.40-1.70 (m, 2 H), 1.80-4.30 (m,17 H), 6.50-6.80(m, 2 H), 6.80-7.10(m, 3 H), 7.23(d, J=8.4 Hz, 2 H),7.37 (s, 1 H), 10.61(brs, 1 H), 11.01 (brs, 1 H); MS (ES) m/z: 320.3((M+2H)²⁺, 100%); 639.4 (MH⁺, 60%); HRMS Calcd. for C₃₀H₃₅N₆O₈S (MH⁺):639.2231. Found: 639.2233.

EXAMPLE 30

(2S)-2-[5-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzylidene)-4-oxo-4,5-dihydro-thiazol-2-ylamino]-pentanedioicacid diethyl ester:

The title compound was prepared from(2S)-2-{5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzylidene]-4-oxo-4,5-dihydro-thiazol-2-ylamino}-pentanedioicacid diethyl ester(which was obtained in Intermediate 34) andN-[5-(2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(whichwas obtained in Intermediate 10) according to the procedures ofIntermediate 18 and Example 1 as a yellowish solid; mp>130° C. (dec.);¹H NMR (300 MHz, DMSO-d₆) δ 1.19(t, J=7.0 Hz, 3 H), 1.22(t, J=7.0 Hz, 3H), 1.70-3.00 (m,14 H), 2.92(s, 3 H), 3.50-3.90 (m, 2 H), 4.05(q, J=7.0Hz, 2 H), 4.14(q, J=7.0 Hz, 2 H), 4.48(dd, J=8.0, 4.3 Hz, 1 H), 4.68(dd,J=8.7, 5.4 Hz, 1 H), 6.82(d, J=8.2 Hz, 1 H), 7.02(dd, J=8.2, 2.0 Hz, 1H), 7.05(d, J=8.9 Hz, 2 H), 7.18(d, J=2.0 Hz, 1 H), 7.40(d, J=8.9 Hz, 2H), 7.50 (s, 1 H); MS (ES) m/z: 359.5 ((M+2H)²⁺, 100%); 718.2 (MH⁺,20%); HRMS Calcd. for C₃₃H₄₄N₆O₉S₂ (MH⁺): 718.2575. Found: 718.2581.

EXAMPLE 31

5-(4-{2-[(2S)-2-Hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethoxy}-benzylidene)-2-piperidin-1-yl-thiazol-4-onehydrochloride salt:

The free base was prepared from[4-(4-oxo-2-piperidin-1-yl-4H-thiazo-5-ylidenemethyl)-phenoxy]-acetaldehydehydrate (which was obtained in Intermediate 39) and(2S)-1-amino-3-(4-hydroxy-phenoxy)-propan-2-ol (which was obtained inIntermediate 5) according to the procedures of Example 1. The free basewas dissolved in methanol/dichloromethane and treated with hydrogenchloride gas. After concentrated the solvents the product was obtainedas a yellowish solid; ¹H NMR (300 MHz, DMSO-d₆) δ 1.50-1.70(m, 6 H),3.00-4.50(m, 13 H), 6.69(d, J=8.9 Hz, 2 H), 6.78(d, J=8.9 Hz, 2 H),7.13(d, J=8.6 Hz, 2 H), 7.60(s, 1 H), 7.62(d, J=8.6 Hz, 2 H), 8.92(brs,1 H), 9.02 (brs, 1 H); MS (ES) m/z: 249.5 ((M+2H)²⁺, 100%); 498.0 (MH⁺,20%); HRMS Calcd. for C₂₆H₃₂N₃O₅S (MH⁺): 498.2063. Found: 498.2039.

EXAMPLE 32

5-{4-[2-((2S)-2-Hydroxy-3-phenoxy-propylamino)-ethoxy]-benzylidene}-2-piperidin-1-yl-thiazol-4-onehydrochloride salt:

The title compound was prepared from[4-(4-oxo-2-piperidin-1-yl-4H-thiazo-5-ylidenemethyl)-phenoxy]-acetaldehydehydrate (which was obtained in Intermediate 39) and(2S)-1-amino-3-phenoxy-propan-2-ol(which was obtained in Intermediate 3)according to the procedures of Example 1 as a yellowish gum; ¹H NMR (300MHz, DMSO-d₆) δ 1.55-1.75(m, 6 H), 2.50-4.50(m, 13 H), 6.90-7.60 (m, 9H), 8.94 (brs, 1 H), 9.22 (brs, 1 H); MS (ES) m/z: 241.5 ((M+2H)²⁺,100%); 482.0 (MH⁺, 30%); HRMS Calcd. for C₂₆H₃₂N₃O₄S (MH⁺): 482.2114.Found: 482.2120.

EXAMPLE 33

N-[2-Hydroxy-5-(1-hydroxy-2-{2-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide:

The title compound was prepared from[4-(4-oxo-2-piperidin-1-yl-4H-thiazo-5-ylidenemethyl)-phenoxy]-acetaldehydehydrate (which was obtained in Intermediate 39) andN-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide(which was obtained in Intermediate 9) according to the procedures ofExample 1 as a yellowish gum; ¹H NMR (300 MHz, DMSO-d₆) δ 1.50-1.70(m, 6H), 2.66(d, J=6.3 Hz, 2 H), 2.93 (s, 3 H), 2.95(t, J=5.4 Hz, 2 H),3.55-3.65(m, 2 H), 3.85-3.95(m, 2 H), 4.01 (t, J=5.4 Hz, 2 H), 4.55(t,J=6.3 Hz, 1 H), 6.82(d, J=8.9 Hz, 2 H), 6.96(dd, J=8.3, 2.0 Hz, 1 H),7.08(d, J=8.9 Hz, 2 H), 7.19(d, J=2.0 Hz, 1 H), 7.56(d, J=8.3 Hz, 1H),7.58 (s, 1 H); MS (ES) m/z: 281.0 ((M+2H)²⁺, 100%); 561.0 (MH⁺, 70%);HRMS Calcd. for C₂₆H₃₃N₄O₆S₂ (MH⁺): 561.1842. Found: 561.1836.

EXAMPLE 34

8-Hydroxy-5-((2S)-2-hydroxy-3-{2-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenoxy]-ethylamino}-propoxy)-3,4-dihydro-1H-quinolin-2-one:

The title compound was prepared from[4-(4-oxo-2-piperidin-1-yl-4H-thiazo-5-ylidenemethyl)-phenoxy]-acetaldehydehydrate (which was obtained in Intermediate 39) and5-((2S)-3-amino-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one(which was obtained in Intermediate 12) according to the procedures ofExample 1 as a yellowish solid; mp>115° C. (dec.); ¹H NMR (300 MHz,DMSO-d₆) δ 1.50-1.70(m, 6 H), 2.38(t, J=7.9 Hz, 2 H), 2.60-2.90 (m, 6H), 2.95(t, J=5.4 Hz, 2 H), 3.50-4.00(m, 5 H), 4.10(t, J=5.4 Hz, 2 H),5.15 (brs, 1 H), 6.44(d, J=8.8 Hz, 1 H), 6.68(d, J=8.8 Hz, 1 H), 7.07(d,J=8.8 Hz, 2 H), 7.58(d, J=8.8 Hz, 2 H), 7.59)s, 1 H), 8.70(s, 1 H), 9.20(brs, 1 H); MS (ES) m/z: 284.0 ((M+2H)²⁺, 100%); 567.0 (MH⁺, 70%); HRMSCalcd. for C₂₉H₃₅N₄O₆S (MH⁺): 567.2277. Found: 567.2254.

What is claimed is:
 1. A compound of formula I having the structure

wherein: A is aryl; X is —OCH₂—, —SCH₂—, or a bond; Y is alkyl of 1-6carbon atoms, alkyloxy of 1-6 carbon atoms, azetidine, pyrrolidine orpiperidine; wherein the nitrogen of the azetidine, pyrrolidine orpiperidine is attached to the adjacent phenyl ring; Z is S, O or NH withthe proviso that when A is aryl, X is a bond and Y is piperidine, Z isnot S; R₁, R₂, and R₃ are each, independently, hydrogen, alkyl of 1-6carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen,trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy,propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino,aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbonatoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino,dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, ordihydroxyphosphorylamino, or two of the three R₁, R₂ or R₃ substituentscombine with the carbon to which each is attached to form a aryl fusedcycloalkyl of 3-8 carbon atoms optionally substituted with an acylaminoor hydroxy group; R₄ is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of1-6 carbon atoms, hydroxy, carboxy, or halogen; R₅ is hydrogen or alkylof 1-6 carbon atoms; R₆ is NR₇R₈; R₇ and R₈ are taken together with thenitrogen to which each is attached to form a piperidinyl, piperazinyl ormorpholinyl moiety optionally substituted with R₉; R₉ is alkyl of 1-6carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6carbon atoms in the alkyl group, hydroxy, halogen, trifluoromethyl,alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxyof 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6carbon atoms per alkyl group, or dihydroxyphosphorylamino; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein A is a phenyl moiety or a napthyl moiety; X is —OCH₂—, or abond; Y is alkyl of 1-6 carbon atoms, alkyloxy of 1-6 carbon atoms, orpiperidine; Z is S; R₁, R₂, and R₃ are each, independently, hydrogen,alkyl of 1-6 carbon atoms, hydroxy, halogen, trifluoromethyl, alkoxy of1-6 carbon atoms, acyloxy of 2-7 carbon atoms, cyano, nitro, amino,aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbonatoms, or alkylsulfonylamino of 1-6 carbon atoms; R₄ is hydrogen; R₅ ishydrogen; R₆ is NR₇R₈; R₇ and R₈ are taken together with the nitrogen towhich each is attached to form a piperidinyl moiety optionallysubstituted with R₉; R₉ is alkyl of 1-6 carbon atoms, or arylalkylhaving 1-6 carbon atoms in the alkyl group; or a pharmaceuticallyacceptable salt thereof.
 3. The compound of claim 1 wherein A is phenyl;X is a bond or —OCH₂—; Y is alkyloxy of 1-6 carbon atoms or piperidine,with the proviso that when X is a bond, Y is not piperidine; Z is S; R₁,R₂, and R₃ are each, independently, hydrogen, alkyl of 1-6 carbon atoms,cycloalkyl of 3-8 carbon atoms, hydroxy, halogen, trifluoromethyl,alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxyof 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6carbon atoms per alkyl group, or dihydroxyphosphorylamino, or two of thethree R₁, R₂ or R₃ substituents combine with the carbon to which each isattached to form a aryl fused cycloalkyl of 3-8 carbon atoms optionallysubstituted with an acylamino or hydroxy group; R₄ is hydrogen, alkyl of1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, carboxy, orhalogen; R₅ is hydrogen or alkyl of 1-6 carbon atoms; or apharmaceutically acceptable salt thereof.
 4. The compound of claim 1,which is a)N-[2-hydroxy-5-((2S)-2-hydroxy-3-{1-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-ylamino}-propoxy)-phenyl]-methanesulfonamide;b)5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-piperidin-1-yl-thiazol-4-one;c)5-{4-[4-((2S)-2-hydroxy-3-phenoxy-propylamino)-piperidin-1-yl]-benzylidene}-2-morpholin-4-yl-thiazol-4-one;d)5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-morpholin-4-yl-thiazol-4-one;e)5-(4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzylidene)-2-(4-methyl-piperazin-1-yl)-thiazol-4-one;f)5-(4-{2-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-ethoxy}-benzylidene)-2-piperidin-1-yl-thiazol-4-one;g)5-{4-[2-((2S)-2-hydroxy-3-phenoxy-propylamino)-ethoxy]-benzylidene}-2-piperidin-1-yl-thiazol-4-one;or h)N-[2-hydroxy-5-(1-hydroxy-2-{2-[4-(4-oxo-2-piperidin-1-yl-4H-thiazol-5-ylidenemethyl)-phenoxy]-ethylamino}-ethyl)-phenyl]-methanesulfonamide;or a pharmaceutically acceptable salt thereof.
 5. A pharmaceuticalcomposition comprising: a) at least one compound of formula I having thestructure

wherein: A is aryl; X is —OCH₂—, —SCH₂—, or a bond; Y is alkyl of 1-6carbon atoms, alkyloxy of 1-6 carbon atoms, azetidine, pyrrolidine orpiperidine; wherein the nitrogen of the azetidine, pyrrolidine orpiperidine is attached to the adjacent phenyl ring; Z is S, O or NH,with the proviso that when A is aryl, X is a bond and Y is piperidine, Zis not S; R₁, R₂, and R₃ are each, independently, hydrogen, alkyl of 1-6carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, halogen,trifluoromethyl, alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy,propargyloxy, acyloxy of 2-7 carbon atoms, cyano, nitro, amino,aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6carbon atoms per alkyl group, formamido, ureido, acylamino of 2-7 carbonatoms, alkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino,dialkyloxyphosphorylamino of 1-6 carbon atoms per alkyl group, ordihydroxyphosphorylamino, or two of the three R₁, R₂ or R₃ substituentscombine with the carbon to which each is attached to form a aryl fusedcycloalkyl of 3-8 carbon atoms optionally substituted with an acylaminoor hydroxy group; R₄ is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of1-6 carbon atoms, hydroxy, carboxy, or halogen; R₅ is hydrogen or alkylof 1-6 carbon atoms; R₆ is NR₇R₈; R₇ and R₈ are taken together with thenitrogen to which each is attached to form a piperidinyl, piperazinyl ormorpholinyl moiety optionally substituted with R₉; R₉ is alkyl of 1-6carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6carbon atoms in the alkyl group, hydroxy, halogen, trifluoromethyl,alkoxy of 1-6 carbon atoms, benzyloxy, allyloxy, propargyloxy, acyloxyof 2-7 carbon atoms, cyano, nitro, amino, aminocarbonyl, alkylamino of1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl group,formamido, ureido, acylamino of 2-7 carbon atoms, alkylsulfonylamino of1-6 carbon atoms, arylsulfonylamino, dialkyloxyphosphorylamino of 1-6carbon atoms per alkyl group, or dihydroxyphosphorylamino; or apharmaceutically acceptable salt thereof; and b) at least onepharmaceutical carrier.